Case 36-2004 — A 23-Day-Old Infant with Hypospadias and Failure to Thrive
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《新英格兰医药杂志》
Presentation of Case
A 23-day-old male infant was admitted to this hospital because of difficulty feeding and failure to thrive.
His weight at birth was 2580 g; he was 45 cm long, the product of an uncomplicated, full-term pregnancy, and born by spontaneous vaginal delivery at another hospital to a 23-year-old woman (gravida 2, para 1). An obstetrical ultrasonographic evaluation at 21 weeks' gestation had shown no abnormalities. At delivery, the amniotic fluid was stained with meconium and there was a nuchal cord. Apgar scores were 2 at one minute and 7 at five minutes. He was briefly intubated and suctioned, and continuous positive airway pressure was administered. Physical examination disclosed severe hypospadias and ambiguous genitalia. The examination revealed no other abnormalities. An evaluation for sepsis was negative. An abdominal ultrasonographic study of the child showed mild left hydronephrosis.
He was initially breast-fed without apparent difficulty, but by the end of the first week of life he began to gag or vomit with attempts to feed, and his interest in feeding appeared to decrease. Bottle-feeding with formula was initiated at one week of life because of his poor weight gain. He continued to have difficulty with feeding, and had a poor sucking reflex, frequent gagging, and nonprojectile emesis. With the institution of small feedings of 1 oz (30 ml) every 45 minutes, he ultimately regained his birth weight at day 21 of life. However, just two days later his weight had fallen to 2495 g, and he was admitted to this hospital.
The patient resided in the Boston area with both parents and a five-year-old half-brother, all of whom were well. The family reported that a cousin of the baby had been born prematurely and had "slow digestion"; a maternal aunt had lost a pregnancy at eight months.
On admission, the infant weighed 2495 g. The temperature was 36.6°C, the pulse 120 beats per minute, and the respiratory rate 36 breaths per minute; the oxygen saturation was 99 percent while he was breathing room air. He appeared alert but small and thin. The face appeared dysmorphic, with wide-set eyes and a flat nasal bridge. The palate was intact and the frenulum was short. The penis was small, and there was severe hypospadias. The remainder of the examination was normal.
On neurologic examination, the infant was aroused with stimulation and had a weak, soft cry. The pupils were equal, round, and reactive to light. He did not track with his eyes and did not turn his head or open his eyes in response to noise. He moved all his extremities. His left leg was flexed most of the time, and his left hand was fisted. He had good head control but had axial and appendicular hypotonia. The deep-tendon reflexes were 3+ in the right arm and hand and left brachioradialis. The left patellar reflex was 3+ and both ankle reflexes were 2+. There was no clonus, and Babinski's reflex was positive bilaterally. An examination of the infant's sensory reflexes showed withdrawal of both legs in response to noxious stimuli, with more reaction on the right than on the left. The results of a complete blood count, the levels of electrolytes, the results of renal- and liver-function tests, and the levels of serum lactate and ammonia were all within normal ranges; the urinalysis and an analysis of the cerebrospinal fluid showed no abnormalities.
On the first two hospital days, the infant continued to feed poorly. The formula was changed and a nasogastric tube was placed, and supplemental feedings were added, to a total of 70 ml every three hours. An upper gastrointestinal series of radiographs showed no evidence of tracheoesophageal fistula, hiatal hernia, aspiration, or pyloric stenosis. There was one episode of gastroesophageal reflux up to the level of the mouth. An ultrasonographic study of the brain showed linear areas of echogenicity in the lenticulostriate area of the right thalamus.
On the second hospital day, a consultant from the department of medical genetics obtained further details of the history, which included the information that the infant's father had two maternal first cousins with "premature aging," but that there was no family history of hypospadias or birth defects. The consultant's examination showed a small, slender baby with decreased subcutaneous fat. He was 53 cm long; the circumference of the head was 33.6 cm. He had a triangular face, widely spaced eyes that slanted upward, a slightly long philtrum, a tight frenulum, a thin upper lip, mild retrognathia, and an intact palate. There was severe perineal hypospadias and a small penis. The scrotum was almost bifid, and both testes were palpable. Clinodactyly of the fifth finger was present on both hands. There was diffuse hypotonia. A soft systolic cardiac murmur, grade 2 of 6, was heard at the left upper sternal border. An examination by a neuro-ophthalmologist disclosed no abnormalities of the eyes.
On the third hospital day, treatment with ranitidine was begun and the formula was changed again. Also on that day, the oxygen saturation decreased to between 70 and 80 percent during feedings and while sleeping, requiring the administration of oxygen with the blow-by technique. He thereafter refused all oral feedings and was fed only by the nasogastric tube.
On the fourth hospital day, labored breathing with retractions and stridor developed. A chest radiograph showed mild interstitial pulmonary edema. The infant was transferred to the intensive care unit, where continuous positive airway pressure was administered. On the sixth day, he was weaned to blow-by oxygen. The nasogastric tube was repositioned to the jejunum and continuous feedings were begun. He had periods of apnea. A magnetic resonance imaging (MRI) scan of the brain obtained on the seventh day showed no congenital abnormalities, no hydrocephalus, and unremarkable thalami without calcification. He weighed 2580 g. Metoclopramide was added to the patient's treatment.
The results of a diagnostic test were received.
Differential Diagnosis
Dr. Joan M. Stoler: This child had intrauterine growth retardation, minor facial dysmorphism, microcephaly, and hypospadias. These facts guided our approach in the evaluation of his failure to thrive.
Definition and Causes of Failure to Thrive
Failure to thrive is not a diagnosis but, rather, a description of a common pediatric problem,1,2 which is cited as the cause of 1 to 5 percent of pediatric hospital admissions.3 The definitions of failure to thrive2,4,5 include a weight that is less than the third percentile for age and sex on more than one occasion, a weight that is less than 80 percent of the ideal weight for the child's age, a decrease of two or more percentile lines on the growth chart, and a weight at two weeks of age that is 10 percent less than the birth weight or an inability to regain the birth weight by three weeks of age.
The causes of failure to thrive are varied and include medical, environmental, and social factors. Causes can be broadly categorized as prenatal or postnatal. In this child, there was evidence of both prenatal and postnatal problems, since he was small at birth and difficulty in feeding developed during the first week of life.
Prenatal Causes of Failure to Thrive
Premature birth, maternal factors (exposure to various drugs, alcohol consumption, cigarette smoking, illness, or malnutrition), chromosomal disorders, single-gene disorders, and genetically associated short stature may all result in low birth weight or in small size for gestational age in an infant who continues to have poor growth (Table 1). One important example of maternal exposure is the use of alcohol during the pregnancy. Consumption of alcohol in large amounts by a pregnant woman can cause the fetal alcohol syndrome, but it can also produce babies who are small for gestational age without the obvious facial features of fetal alcohol syndrome. In fact, so-called moderate alcohol consumption (two drinks per day) can have marked effects on fetal growth.6,7 This potentially harmful factor is often overlooked, even when the exposure is known.8
Table 1. Prenatal Causes of Failure to Thrive.
Maternal illnesses that affect fetal growth include hypertension and infectious diseases, such as rubella, cytomegalovirus, syphilis, and less commonly, toxoplasmosis and herpes simplex virus. Typically, there will be signs in the baby such as hepatosplenomegaly, cataracts, retinopathy, and microcephaly, as well as abnormal results of laboratory tests (hematologic abnormalities, abnormalities of the central nervous system, or hearing deficits). In this case, a thorough pregnancy history, which included possible exposures such as alcohol consumption, use of medications, and illnesses during the pregnancy, revealed no exposures that should have affected the infant.
Chromosomal abnormalities and single-gene disorders encompass a large group of disorders causing intrauterine growth retardation, subsequent poor growth, and often a characteristic pattern of birth defects and minor anomalies. Genetic and chromosomal causes are implicated in about 10 percent of cases in which children are hospitalized for failure to thrive.9 Chromosomal abnormalities are present in 50 percent of all spontaneously aborted fetuses,10 in 0.2 percent of newborns,11 and in approximately 3 to 8 percent of children with birth defects.12 The particular pattern of anomalies may give clues to the specific genetic abnormality. As for single-gene disorders, in the Online Mendelian Inheritance in Man database, the search term "failure to thrive" results in a list of more than 50 entries. This patient's parents reported no hereditary illnesses in the family; a half-brother and both parents were normal. However, the finding of multiple congenital abnormalities in the infant strongly suggested a genetic defect.
Postnatal Causes of Failure to Thrive
Postnatal causes of failure to thrive can be subdivided according to whether the child's primary problem is inadequate energy intake, impaired ability to make use of the intake, or increased energy demands (Table 2). Some conditions fit into more than one of these categories. For example, children with congenital heart disease have an impaired food intake because of fatigue and also increased metabolic demands. In this patient, the physical examination and observation of feeding revealed that the muscles were hypotonic and his sucking ability was poor. His muscle strength and level of alertness were normal. The problem was poor intake compounded by vomiting after even small feedings, a pattern that suggests reflux.
Table 2. Postnatal Causes of Failure to Thrive.
Further testing in a case such as this depends on what the history, physical examination, and observation have shown (Table 3). The results of the state newborn screening tests should be obtained. Currently, the Massachusetts newborn screening program tests for 7 metabolic disorders as well as congenital hypothyroidism and hemoglobinopathies, with optional screening for 22 more diseases, including cystic fibrosis. The results of the newborn screening were negative in this infant.
Table 3. Laboratory Evaluation of Failure to Thrive.
The Differential Diagnosis in This Case
After the initial evaluation, I thought that a genetic abnormality was the most likely cause of this child's problems. The differential diagnosis included a chromosomal abnormality, the Smith–Lemli–Opitz syndrome, and the Opitz G/BBB syndrome, also called the hypertelorism–hypospadias syndrome.
Children with the Smith–Lemli–Opitz syndrome typically have failure to thrive, genital abnormalities (in males), microcephaly, syndactyly of the second and third toes, and polydactyly. They have a particular facial appearance that includes epicanthal folds, posteriorly rotated ears, ptosis, a small pug nose, a broad alveolar ridge, and micrognathia.13,14,15 This syndrome is an autosomal recessive condition due to a deficiency of 7-dehydrocholesterol reductase, with the resultant increase in 7-dehydrocholesterol, a precursor to cholesterol. The gene is called DHCR7, and it is located on chromosome 11. The Smith–Lemli–Opitz syndrome is not uncommon, with an incidence of 1 in 20,000 to 1 in 40,000 among people of European ancestry.16 The diagnosis is determined by a measurement of the levels of serum 7-dehydrocholesterol. This child did not have the characteristic facial features or findings in the extremities.
The hypertelorism–hypospadias syndrome consists of hypertelorism; upward-slanting palpebral fissures with epicanthal folds; a broad, flat nasal bridge; a cleft lip with or without a cleft palate; and male genital abnormalities that can include hypospadias, cryptorchidism, a bifid scrotum, and initial failure to thrive.17,18 The failure to thrive is caused by swallowing difficulties, with recurrent aspiration due to anomalies of the larynx and of the epiglottis or the trachea or both — most notably laryngotracheal clefts. There are two types of the hypertelorism–hypospadias syndrome, an X-linked form and an autosomal dominant form linked to chromosomal locus 22q11.2. This baby had hypertelorism, genital abnormalities, and failure to thrive that was due to poor food intake. However, he did not have a cleft lip and was not known to have a laryngeal or tracheal abnormality.
Genetic testing was recommended, including a karyotype analysis, fluorescence in situ hybridization (FISH) to look for the deletion at 22q11.2, and measurement of the serum level of 7-dehydrocholesterol. The results of FISH and the 7-dehydrocholesterol level were within normal limits.
Pathological Discussion
Dr. Natalia T. Leach: The chromosomal analysis of the patient's peripheral-blood lymphocytes revealed a structurally abnormal chromosome 16, with additional material of unknown origin on the distal part of the p (short) arm in every metaphase analyzed (Figure 1A). A karyotype of 46,XY,add(16)(p13) was initially assigned, and an analysis of parental chromosomes was requested to determine whether the abnormal chromosome was new or familial.
Figure 1. Karyotype of the Patient and the Inverted Chromosome 16 of his Father.
The karyotype of the patient shows the presence of an abnormal chromosome 16 (Panel A, arrow). The diagram (Panel B) shows a normal chromosome 16 (left), an inverted segment (center, curved arrow), and an abnormal chromosome 16 with a pericentric inversion, with the breakpoints in bands p13 and q22 (right). Staining of the father's chromosome 16 with two different stains (Panel C, Giemsa, and Panel D, quinacrine) shows one normal chromosome 16 (left in each pair) and one with a pericentric inversion, inv(16) (right in each pair).
After the findings had been reported to the parents, the baby's father stated that he and several members of his family had an abnormality of chromosome 16. It was also learned that the patient's mother had sought prenatal counseling with Dr. Stoler because of this family history. However, she had not known the details of the abnormality, and she had not kept the follow-up appointments, despite repeated attempts to contact her. When the mother was asked why she had not returned for genetic testing, she replied that she had not wanted to have to think about the possibility of ending the pregnancy.
The genetics team then discovered that this family had been extensively studied 20 years previously by our laboratory.19 The patient's father had been karyotyped at two years of age, and a pericentric inversion of chromosome 16, with breakpoints in bands p13 and q22 (the inverted segment includes the centromere), had been found with the use of quinacrine and Giemsa (GTG banding) (Figure 1C and Figure 1D). (Giemsa and fluorescent dye quinacrine are DNA-binding agents that produce chromosome-specific banding patterns used for chromosomal analysis.) Therefore, the final karyotype of the infant was reported as 46,XY,rec(16)dup(16q)inv(16)(p13q22)pat. The nomenclature reflects the fact that the abnormal chromosome 16 arose as a result of a recombination between the normal and the inverted chromosome 16 in the patient's father.
Balanced inversions can have clinical consequences if the chromosomal breakpoints either disrupt a gene or separate it (or a group of genes) from a regulatory element. Neither scenario appears to apply to this particular inversion of chromosome 16, because of the normal phenotype in the patient's father and in the other carriers in this family. The primary concern with respect to the carriers is the risk of having chromosomally abnormal offspring because of the production of unbalanced gametes. This occurs as a result of an uneven number of recombination events between the normal and inverted chromosomes, within the inverted region.
During chromosome pairing in meiosis, a loop is formed in the chromosomal region that is involved in an inversion, to allow for optimal alignment of the inverted chromosome and its normal homologue (Figure 2). For example, a single crossing-over event within the inversion loop would result in four different gametes: one with a normal chromosome, another with an inverted chromosome, and two with different recombinant chromosomes with partial duplications (producing partial trisomy in the offspring) and deletions (producing partial monosomy in the offspring). The risk of having an abnormal offspring depends on the size and type of inversion. Large pericentric inversions have a higher likelihood of recombination and a greater risk of producing viable recombinant offspring because a smaller genetic imbalance is created.20
Figure 2. Meiotic Recombination within the Inverted Region in Persons with Pericentric Inversion of Chromosome 16.
There is a loop formation (left) during chromosomal pairing in meiosis to allow for optimal alignment of the inverted chromosome and its normal homologue, as demonstrated here with numbers depicting different chromosomal regions. A single crossing-over event within the inversion loop (the locus of exchange is marked in red) would result in four different gametes (right): one with a normal chromosome 16 (nl), another with an inverted chromosome 16 (inv), and two with different recombinant chromosomes (rec). The latter two recombinant chromosomes would have partial duplications (producing partial trisomy in the offspring) and deletions (producing partial monosomy in the offspring).
In the study of the father's family, karyotype analyses of members of three generations were performed19 (Figure 3). Multiple carriers of the inversion of chromosome 16, as well as carriers of the recombinant chromosome 16, were identified, including two people with cytogenetically identified recombinant chromosome 16: an infant girl with congenital heart disease and pulmonary hypoplasia, who died at six hours of age, and an aborted male fetus, with massive hydrocephalus and a single umbilical artery (who was a sibling to the father of the infant in this case). Recombinant chromosome 16, in association with multiple anomalies, was suspected in two other deceased family members.
Figure 3. Pedigree of the Patient's Father.
The patient is designated by the arrow. The infants who had multiple birth defects and had the recombinant chromosome are depicted in black; those with multiple birth defects in whom karyotyping was not performed are depicted in yellow. Asymptomatic carriers of the inversion are depicted in blue. The persons depicted by a question mark have not had karyotype analysis performed. One of the father's brothers and the children of the brother who is a carrier have not been tested. Square symbols depict male family members, circles female family members, and the diagonal lines family members who have died. White circles or squares indicate family members who do not have the inversion, and triangles a spontaneous miscarriage.
Although the GTG-banded appearance of the recombinant chromosome 16 in the two patients described by Bianchi et al.19 and of that in this infant appear to be identical, molecular characterization of the recombinant chromosome 16 in the study by Bianchi et al. showed differences in the breakpoint regions. This may explain the variation in the clinical phenotype among patients with recombinant chromosome 16. A cytogenetically identical inv(16)(p13q22) is found in some cases of acute myeloid leukemia as an acquired abnormality. However, the delineation of the breakpoints of this familial chromosome 16 inversion showed that this constitutional rearrangement has distinctly different breakpoints from the inversion found in acute myeloid leukemia.21
A number of patients with the chromosomal imbalances known as partial trisomy 16 and partial monosomy 16 have been described in the literature, each having a number of clinical features that overlap those of our patient with the recombinant chromosome 16 and with the other patients with the recombinant chromosome described in the study of this family. However, a strict comparison between these groups of patients is hindered by the fact that partial trisomy or monosomy 16 is usually accompanied by partial trisomy or monosomy of other chromosomes.
Discussion of Management
Dr. Stoler: The first article published on this family stated that "in the family described here, there are at least 6 young children in generation III who carry the inv(16). They are all at risk for developing abnormal recombinants in their gametes. Although none of the individuals has yet reached reproductive age, we have met with all of their parents to provide genetic counseling. As tragically demonstrated in this family, prenatal diagnosis should be offered to any individual known to carry inv(16)."19 Despite this, the father of this baby did not fully comprehend the implications. He had assumed that since he himself did not have any medical problems and since his brother, also a carrier of the inv(16) mutation, had two normal children, the mutation did not pose a substantial risk. He also was unaware that his mother had terminated a pregnancy as reported in the family study19 (Figure 3). This case demonstrates that information may not be conveyed accurately within families and raises the issue of how we can better convey this information.
Poor feeding and lack of weight gain have continued to be problems for this child. When he was three months of age, a gastrostomy tube was placed, after which the patient had continuous vomiting with large-volume feedings; one month later a laparoscopic Nissen fundoplication was performed. His reflux resolved and he is now able to tolerate full feedings through his gastrostomy tube.
At an examination at the age of eight months, he showed some developmental progress. He was alert and interactive and sat when propped in a sitting position. However, his weight was 7600 g (5th percentile), and he was 65 cm long (10th percentile).
Dr. Nancy Lee Harris (Pathology): In addition to the topic of genetic counseling that this case raises, the child has important medical and surgical problems. Dr. Donahoe, could you describe the plan for management of the severe hypospadias?
Dr. Patricia K. Donahoe: The patient's phallus at birth measured 2.5 cm long (Figure 4). The phallus of a normal full-term newborn is 3.5 cm, plus or minus 0.5 cm. A penoscrotal urethral meatus was located at the base of the phallus. Each scrotum housed a testis of normal size. There was no evidence of retained mullerian structures either on physical examination or on ultrasonographic study. The patient's testosterone levels are low and will be further evaluated with human chorionic gonadotropin stimulation. The levels of mullerian-inhibiting substance and gonadotropin are normal. The infant will undergo a two-stage repair, with an expected good cosmetic and functional result by two years of age.
Figure 4. Hypospadias and Ambiguous Genitalia in the Patient at Eight Months of Age.
The patient's phallus at birth measured 2.5 cm, as calculated by adding two planes of measurements along the dorsum from the symphysis pubis to the distal tip. The diameter was 1 cm. A penoscrotal urethral meatus was located at the base of the phallus. Each scrotum housed a testis of normal size.
Final Diagnosis
Congenital abnormalities due to a chromosomal imbalance, karyotype 46,XY,rec(16)dup(16q)inv(16)(p13q22)pat, resulting from the recombination between the normal chromosome 16 and the inverted chromosome 16 in the patient's father.
Source Information
From the Departments of Medical Genetics (J.M.S.) and Pediatric Surgery (P.K.D.), Massachusetts General Hospital; the Department of Pathology, Brigham and Women's Hospital (N.T.L.); and the Departments of Pediatrics (J.M.S.), Pathology (N.T.L.), and Surgery (P.K.D.), Harvard Medical School — all in Boston.
References
Marcovitch H. Failure to thrive. BMJ 1994;308:35-38.
Kirkland RT. Failure to thrive. In: McMillan JA, DeAngelis CA, Feigin RD, Warchaw JB, eds. Oski's pediatrics: principles and practice. 3rd ed. Philadelphia: Lippincott-Raven, 1999:752-5.
Olsen EM, Johannsen TH, Moltesen B, Skovgaard AM. Failure to thrive among hospitalized 0-2 year-old children. Ugeskr Laeger 2002;164:5654-5658.
Wilcox WD, Nieburg P, Miller DS. Failure to thrive: a continuing problem of definition. Clin Pediatr (Phila) 1989;28:391-394.
Frank DA, Zeisel SH. Failure to thrive. Pediatr Clin North Am 1988;35:1187-1206.
Mills JK, Graubard BI, Harley EE, Rhoads GG, Berendes HW. Maternal alcohol consumption and birth weight: how much drinking during pregnancy is safe? JAMA 1984;252:1875-1879.
Hanson JW, Streissguth AP, Smith DW. The effects of moderate alcohol consumption during pregnancy on fetal growth and morphogenesis. J Pediatr 1978;92:457-460.
Stoler JM, Holmes LB. Under-recognition of prenatal alcohol effects in infants of known alcohol abusing women. J Pediatr 1999;135:430-436.
Homer C, Ludwig S. Categorization of etiology of failure to thrive. Am J Dis Child 1981;135:848-851.
Hassold TJ, Takaesu N. Analysis of non-disjunction in human trisomic spontaneous abortions. In: Hassold TJ, Epstein CJ, eds. Molecular and cytogenetic studies of non-disjunction: proceedings of the Fifth Annual National Down Syndrome Society Symposium held in New York, N.Y., December 1-2, 1988. New York: Alan R. Liss, 1989:115-34.
Jacobs PA, Browne C, Gregson N, Joyce C, White H. Estimates of the frequency of chromosome abnormalities detectable in unselected newborns using moderate levels of banding. J Med Genet 1992;29:103-108.
Centeno Malfaz F, Beltran Perez A, Ruiz Labarga C, Centeno Robles T, Macias Pardal J, Martin Bermejo M. Chromosome aberrations in malformed newborns. An Esp Pediatr 2001;54:582-587.
Tint GS, Irons M, Elias ER, et al. Defective cholesterol biosynthesis associated with the Smith-Lemli-Opitz syndrome. N Engl J Med 1994;330:107-113.
Opitz JM. RSH/SLO ("Smith-Lemli-Opitz") syndrome: historical, genetic, and developmental considerations. Am J Med Genet 1994;50:344-346.
Joseph DB, Uehling DT, Gilbert E, Laxova R. Genitourinary abnormalities associated with the Smith-Lemli-Opitz syndrome. J Urol 1987;137:719-721.
Moebius FF, Fitzky BU, Lee JN, Paik YK, Glossmann H. Molecular cloning and expression of the human delta7-sterol reductase. Proc Natl Acad Sci U S A 1998;95:1899-1902.
Robin NH, Feldman GJ, Aronson AL, et al. Opitz syndrome is genetically heterogeneous, with one locus on Xp22, and a second locus on 22q11.2. Nat Genet 1995;11:459-461.
Gonzales CH, Herrmann J, Opitz JM. The hypertelorism-hypospadias (BBB) syndrome. Eur J Pediatr 1977;125:1-13.
Bianchi DW, Nicholls RD, Russell KA, Miller WA, Ellin M, Lage JM. Pericentric inversion of chromosome 16 in a large kindred: spectrum of morbidity and mortality in offspring. Am J Med Genet 1992;43:791-795.
Gardner RJM, Sutherland GR. Chromosome abnormalities and genetic counseling. New York: Oxford University Press, 1996:137-50.
Stallings RL, Bianchi DW. FISH mapping of a human chromosome 16 constitutional pericentric inversion inv(16)(p13q22) found in a large kindred. Am J Med Genet 1994;52:346-348.(Joan M. Stoler, M.D., Nat)
A 23-day-old male infant was admitted to this hospital because of difficulty feeding and failure to thrive.
His weight at birth was 2580 g; he was 45 cm long, the product of an uncomplicated, full-term pregnancy, and born by spontaneous vaginal delivery at another hospital to a 23-year-old woman (gravida 2, para 1). An obstetrical ultrasonographic evaluation at 21 weeks' gestation had shown no abnormalities. At delivery, the amniotic fluid was stained with meconium and there was a nuchal cord. Apgar scores were 2 at one minute and 7 at five minutes. He was briefly intubated and suctioned, and continuous positive airway pressure was administered. Physical examination disclosed severe hypospadias and ambiguous genitalia. The examination revealed no other abnormalities. An evaluation for sepsis was negative. An abdominal ultrasonographic study of the child showed mild left hydronephrosis.
He was initially breast-fed without apparent difficulty, but by the end of the first week of life he began to gag or vomit with attempts to feed, and his interest in feeding appeared to decrease. Bottle-feeding with formula was initiated at one week of life because of his poor weight gain. He continued to have difficulty with feeding, and had a poor sucking reflex, frequent gagging, and nonprojectile emesis. With the institution of small feedings of 1 oz (30 ml) every 45 minutes, he ultimately regained his birth weight at day 21 of life. However, just two days later his weight had fallen to 2495 g, and he was admitted to this hospital.
The patient resided in the Boston area with both parents and a five-year-old half-brother, all of whom were well. The family reported that a cousin of the baby had been born prematurely and had "slow digestion"; a maternal aunt had lost a pregnancy at eight months.
On admission, the infant weighed 2495 g. The temperature was 36.6°C, the pulse 120 beats per minute, and the respiratory rate 36 breaths per minute; the oxygen saturation was 99 percent while he was breathing room air. He appeared alert but small and thin. The face appeared dysmorphic, with wide-set eyes and a flat nasal bridge. The palate was intact and the frenulum was short. The penis was small, and there was severe hypospadias. The remainder of the examination was normal.
On neurologic examination, the infant was aroused with stimulation and had a weak, soft cry. The pupils were equal, round, and reactive to light. He did not track with his eyes and did not turn his head or open his eyes in response to noise. He moved all his extremities. His left leg was flexed most of the time, and his left hand was fisted. He had good head control but had axial and appendicular hypotonia. The deep-tendon reflexes were 3+ in the right arm and hand and left brachioradialis. The left patellar reflex was 3+ and both ankle reflexes were 2+. There was no clonus, and Babinski's reflex was positive bilaterally. An examination of the infant's sensory reflexes showed withdrawal of both legs in response to noxious stimuli, with more reaction on the right than on the left. The results of a complete blood count, the levels of electrolytes, the results of renal- and liver-function tests, and the levels of serum lactate and ammonia were all within normal ranges; the urinalysis and an analysis of the cerebrospinal fluid showed no abnormalities.
On the first two hospital days, the infant continued to feed poorly. The formula was changed and a nasogastric tube was placed, and supplemental feedings were added, to a total of 70 ml every three hours. An upper gastrointestinal series of radiographs showed no evidence of tracheoesophageal fistula, hiatal hernia, aspiration, or pyloric stenosis. There was one episode of gastroesophageal reflux up to the level of the mouth. An ultrasonographic study of the brain showed linear areas of echogenicity in the lenticulostriate area of the right thalamus.
On the second hospital day, a consultant from the department of medical genetics obtained further details of the history, which included the information that the infant's father had two maternal first cousins with "premature aging," but that there was no family history of hypospadias or birth defects. The consultant's examination showed a small, slender baby with decreased subcutaneous fat. He was 53 cm long; the circumference of the head was 33.6 cm. He had a triangular face, widely spaced eyes that slanted upward, a slightly long philtrum, a tight frenulum, a thin upper lip, mild retrognathia, and an intact palate. There was severe perineal hypospadias and a small penis. The scrotum was almost bifid, and both testes were palpable. Clinodactyly of the fifth finger was present on both hands. There was diffuse hypotonia. A soft systolic cardiac murmur, grade 2 of 6, was heard at the left upper sternal border. An examination by a neuro-ophthalmologist disclosed no abnormalities of the eyes.
On the third hospital day, treatment with ranitidine was begun and the formula was changed again. Also on that day, the oxygen saturation decreased to between 70 and 80 percent during feedings and while sleeping, requiring the administration of oxygen with the blow-by technique. He thereafter refused all oral feedings and was fed only by the nasogastric tube.
On the fourth hospital day, labored breathing with retractions and stridor developed. A chest radiograph showed mild interstitial pulmonary edema. The infant was transferred to the intensive care unit, where continuous positive airway pressure was administered. On the sixth day, he was weaned to blow-by oxygen. The nasogastric tube was repositioned to the jejunum and continuous feedings were begun. He had periods of apnea. A magnetic resonance imaging (MRI) scan of the brain obtained on the seventh day showed no congenital abnormalities, no hydrocephalus, and unremarkable thalami without calcification. He weighed 2580 g. Metoclopramide was added to the patient's treatment.
The results of a diagnostic test were received.
Differential Diagnosis
Dr. Joan M. Stoler: This child had intrauterine growth retardation, minor facial dysmorphism, microcephaly, and hypospadias. These facts guided our approach in the evaluation of his failure to thrive.
Definition and Causes of Failure to Thrive
Failure to thrive is not a diagnosis but, rather, a description of a common pediatric problem,1,2 which is cited as the cause of 1 to 5 percent of pediatric hospital admissions.3 The definitions of failure to thrive2,4,5 include a weight that is less than the third percentile for age and sex on more than one occasion, a weight that is less than 80 percent of the ideal weight for the child's age, a decrease of two or more percentile lines on the growth chart, and a weight at two weeks of age that is 10 percent less than the birth weight or an inability to regain the birth weight by three weeks of age.
The causes of failure to thrive are varied and include medical, environmental, and social factors. Causes can be broadly categorized as prenatal or postnatal. In this child, there was evidence of both prenatal and postnatal problems, since he was small at birth and difficulty in feeding developed during the first week of life.
Prenatal Causes of Failure to Thrive
Premature birth, maternal factors (exposure to various drugs, alcohol consumption, cigarette smoking, illness, or malnutrition), chromosomal disorders, single-gene disorders, and genetically associated short stature may all result in low birth weight or in small size for gestational age in an infant who continues to have poor growth (Table 1). One important example of maternal exposure is the use of alcohol during the pregnancy. Consumption of alcohol in large amounts by a pregnant woman can cause the fetal alcohol syndrome, but it can also produce babies who are small for gestational age without the obvious facial features of fetal alcohol syndrome. In fact, so-called moderate alcohol consumption (two drinks per day) can have marked effects on fetal growth.6,7 This potentially harmful factor is often overlooked, even when the exposure is known.8
Table 1. Prenatal Causes of Failure to Thrive.
Maternal illnesses that affect fetal growth include hypertension and infectious diseases, such as rubella, cytomegalovirus, syphilis, and less commonly, toxoplasmosis and herpes simplex virus. Typically, there will be signs in the baby such as hepatosplenomegaly, cataracts, retinopathy, and microcephaly, as well as abnormal results of laboratory tests (hematologic abnormalities, abnormalities of the central nervous system, or hearing deficits). In this case, a thorough pregnancy history, which included possible exposures such as alcohol consumption, use of medications, and illnesses during the pregnancy, revealed no exposures that should have affected the infant.
Chromosomal abnormalities and single-gene disorders encompass a large group of disorders causing intrauterine growth retardation, subsequent poor growth, and often a characteristic pattern of birth defects and minor anomalies. Genetic and chromosomal causes are implicated in about 10 percent of cases in which children are hospitalized for failure to thrive.9 Chromosomal abnormalities are present in 50 percent of all spontaneously aborted fetuses,10 in 0.2 percent of newborns,11 and in approximately 3 to 8 percent of children with birth defects.12 The particular pattern of anomalies may give clues to the specific genetic abnormality. As for single-gene disorders, in the Online Mendelian Inheritance in Man database, the search term "failure to thrive" results in a list of more than 50 entries. This patient's parents reported no hereditary illnesses in the family; a half-brother and both parents were normal. However, the finding of multiple congenital abnormalities in the infant strongly suggested a genetic defect.
Postnatal Causes of Failure to Thrive
Postnatal causes of failure to thrive can be subdivided according to whether the child's primary problem is inadequate energy intake, impaired ability to make use of the intake, or increased energy demands (Table 2). Some conditions fit into more than one of these categories. For example, children with congenital heart disease have an impaired food intake because of fatigue and also increased metabolic demands. In this patient, the physical examination and observation of feeding revealed that the muscles were hypotonic and his sucking ability was poor. His muscle strength and level of alertness were normal. The problem was poor intake compounded by vomiting after even small feedings, a pattern that suggests reflux.
Table 2. Postnatal Causes of Failure to Thrive.
Further testing in a case such as this depends on what the history, physical examination, and observation have shown (Table 3). The results of the state newborn screening tests should be obtained. Currently, the Massachusetts newborn screening program tests for 7 metabolic disorders as well as congenital hypothyroidism and hemoglobinopathies, with optional screening for 22 more diseases, including cystic fibrosis. The results of the newborn screening were negative in this infant.
Table 3. Laboratory Evaluation of Failure to Thrive.
The Differential Diagnosis in This Case
After the initial evaluation, I thought that a genetic abnormality was the most likely cause of this child's problems. The differential diagnosis included a chromosomal abnormality, the Smith–Lemli–Opitz syndrome, and the Opitz G/BBB syndrome, also called the hypertelorism–hypospadias syndrome.
Children with the Smith–Lemli–Opitz syndrome typically have failure to thrive, genital abnormalities (in males), microcephaly, syndactyly of the second and third toes, and polydactyly. They have a particular facial appearance that includes epicanthal folds, posteriorly rotated ears, ptosis, a small pug nose, a broad alveolar ridge, and micrognathia.13,14,15 This syndrome is an autosomal recessive condition due to a deficiency of 7-dehydrocholesterol reductase, with the resultant increase in 7-dehydrocholesterol, a precursor to cholesterol. The gene is called DHCR7, and it is located on chromosome 11. The Smith–Lemli–Opitz syndrome is not uncommon, with an incidence of 1 in 20,000 to 1 in 40,000 among people of European ancestry.16 The diagnosis is determined by a measurement of the levels of serum 7-dehydrocholesterol. This child did not have the characteristic facial features or findings in the extremities.
The hypertelorism–hypospadias syndrome consists of hypertelorism; upward-slanting palpebral fissures with epicanthal folds; a broad, flat nasal bridge; a cleft lip with or without a cleft palate; and male genital abnormalities that can include hypospadias, cryptorchidism, a bifid scrotum, and initial failure to thrive.17,18 The failure to thrive is caused by swallowing difficulties, with recurrent aspiration due to anomalies of the larynx and of the epiglottis or the trachea or both — most notably laryngotracheal clefts. There are two types of the hypertelorism–hypospadias syndrome, an X-linked form and an autosomal dominant form linked to chromosomal locus 22q11.2. This baby had hypertelorism, genital abnormalities, and failure to thrive that was due to poor food intake. However, he did not have a cleft lip and was not known to have a laryngeal or tracheal abnormality.
Genetic testing was recommended, including a karyotype analysis, fluorescence in situ hybridization (FISH) to look for the deletion at 22q11.2, and measurement of the serum level of 7-dehydrocholesterol. The results of FISH and the 7-dehydrocholesterol level were within normal limits.
Pathological Discussion
Dr. Natalia T. Leach: The chromosomal analysis of the patient's peripheral-blood lymphocytes revealed a structurally abnormal chromosome 16, with additional material of unknown origin on the distal part of the p (short) arm in every metaphase analyzed (Figure 1A). A karyotype of 46,XY,add(16)(p13) was initially assigned, and an analysis of parental chromosomes was requested to determine whether the abnormal chromosome was new or familial.
Figure 1. Karyotype of the Patient and the Inverted Chromosome 16 of his Father.
The karyotype of the patient shows the presence of an abnormal chromosome 16 (Panel A, arrow). The diagram (Panel B) shows a normal chromosome 16 (left), an inverted segment (center, curved arrow), and an abnormal chromosome 16 with a pericentric inversion, with the breakpoints in bands p13 and q22 (right). Staining of the father's chromosome 16 with two different stains (Panel C, Giemsa, and Panel D, quinacrine) shows one normal chromosome 16 (left in each pair) and one with a pericentric inversion, inv(16) (right in each pair).
After the findings had been reported to the parents, the baby's father stated that he and several members of his family had an abnormality of chromosome 16. It was also learned that the patient's mother had sought prenatal counseling with Dr. Stoler because of this family history. However, she had not known the details of the abnormality, and she had not kept the follow-up appointments, despite repeated attempts to contact her. When the mother was asked why she had not returned for genetic testing, she replied that she had not wanted to have to think about the possibility of ending the pregnancy.
The genetics team then discovered that this family had been extensively studied 20 years previously by our laboratory.19 The patient's father had been karyotyped at two years of age, and a pericentric inversion of chromosome 16, with breakpoints in bands p13 and q22 (the inverted segment includes the centromere), had been found with the use of quinacrine and Giemsa (GTG banding) (Figure 1C and Figure 1D). (Giemsa and fluorescent dye quinacrine are DNA-binding agents that produce chromosome-specific banding patterns used for chromosomal analysis.) Therefore, the final karyotype of the infant was reported as 46,XY,rec(16)dup(16q)inv(16)(p13q22)pat. The nomenclature reflects the fact that the abnormal chromosome 16 arose as a result of a recombination between the normal and the inverted chromosome 16 in the patient's father.
Balanced inversions can have clinical consequences if the chromosomal breakpoints either disrupt a gene or separate it (or a group of genes) from a regulatory element. Neither scenario appears to apply to this particular inversion of chromosome 16, because of the normal phenotype in the patient's father and in the other carriers in this family. The primary concern with respect to the carriers is the risk of having chromosomally abnormal offspring because of the production of unbalanced gametes. This occurs as a result of an uneven number of recombination events between the normal and inverted chromosomes, within the inverted region.
During chromosome pairing in meiosis, a loop is formed in the chromosomal region that is involved in an inversion, to allow for optimal alignment of the inverted chromosome and its normal homologue (Figure 2). For example, a single crossing-over event within the inversion loop would result in four different gametes: one with a normal chromosome, another with an inverted chromosome, and two with different recombinant chromosomes with partial duplications (producing partial trisomy in the offspring) and deletions (producing partial monosomy in the offspring). The risk of having an abnormal offspring depends on the size and type of inversion. Large pericentric inversions have a higher likelihood of recombination and a greater risk of producing viable recombinant offspring because a smaller genetic imbalance is created.20
Figure 2. Meiotic Recombination within the Inverted Region in Persons with Pericentric Inversion of Chromosome 16.
There is a loop formation (left) during chromosomal pairing in meiosis to allow for optimal alignment of the inverted chromosome and its normal homologue, as demonstrated here with numbers depicting different chromosomal regions. A single crossing-over event within the inversion loop (the locus of exchange is marked in red) would result in four different gametes (right): one with a normal chromosome 16 (nl), another with an inverted chromosome 16 (inv), and two with different recombinant chromosomes (rec). The latter two recombinant chromosomes would have partial duplications (producing partial trisomy in the offspring) and deletions (producing partial monosomy in the offspring).
In the study of the father's family, karyotype analyses of members of three generations were performed19 (Figure 3). Multiple carriers of the inversion of chromosome 16, as well as carriers of the recombinant chromosome 16, were identified, including two people with cytogenetically identified recombinant chromosome 16: an infant girl with congenital heart disease and pulmonary hypoplasia, who died at six hours of age, and an aborted male fetus, with massive hydrocephalus and a single umbilical artery (who was a sibling to the father of the infant in this case). Recombinant chromosome 16, in association with multiple anomalies, was suspected in two other deceased family members.
Figure 3. Pedigree of the Patient's Father.
The patient is designated by the arrow. The infants who had multiple birth defects and had the recombinant chromosome are depicted in black; those with multiple birth defects in whom karyotyping was not performed are depicted in yellow. Asymptomatic carriers of the inversion are depicted in blue. The persons depicted by a question mark have not had karyotype analysis performed. One of the father's brothers and the children of the brother who is a carrier have not been tested. Square symbols depict male family members, circles female family members, and the diagonal lines family members who have died. White circles or squares indicate family members who do not have the inversion, and triangles a spontaneous miscarriage.
Although the GTG-banded appearance of the recombinant chromosome 16 in the two patients described by Bianchi et al.19 and of that in this infant appear to be identical, molecular characterization of the recombinant chromosome 16 in the study by Bianchi et al. showed differences in the breakpoint regions. This may explain the variation in the clinical phenotype among patients with recombinant chromosome 16. A cytogenetically identical inv(16)(p13q22) is found in some cases of acute myeloid leukemia as an acquired abnormality. However, the delineation of the breakpoints of this familial chromosome 16 inversion showed that this constitutional rearrangement has distinctly different breakpoints from the inversion found in acute myeloid leukemia.21
A number of patients with the chromosomal imbalances known as partial trisomy 16 and partial monosomy 16 have been described in the literature, each having a number of clinical features that overlap those of our patient with the recombinant chromosome 16 and with the other patients with the recombinant chromosome described in the study of this family. However, a strict comparison between these groups of patients is hindered by the fact that partial trisomy or monosomy 16 is usually accompanied by partial trisomy or monosomy of other chromosomes.
Discussion of Management
Dr. Stoler: The first article published on this family stated that "in the family described here, there are at least 6 young children in generation III who carry the inv(16). They are all at risk for developing abnormal recombinants in their gametes. Although none of the individuals has yet reached reproductive age, we have met with all of their parents to provide genetic counseling. As tragically demonstrated in this family, prenatal diagnosis should be offered to any individual known to carry inv(16)."19 Despite this, the father of this baby did not fully comprehend the implications. He had assumed that since he himself did not have any medical problems and since his brother, also a carrier of the inv(16) mutation, had two normal children, the mutation did not pose a substantial risk. He also was unaware that his mother had terminated a pregnancy as reported in the family study19 (Figure 3). This case demonstrates that information may not be conveyed accurately within families and raises the issue of how we can better convey this information.
Poor feeding and lack of weight gain have continued to be problems for this child. When he was three months of age, a gastrostomy tube was placed, after which the patient had continuous vomiting with large-volume feedings; one month later a laparoscopic Nissen fundoplication was performed. His reflux resolved and he is now able to tolerate full feedings through his gastrostomy tube.
At an examination at the age of eight months, he showed some developmental progress. He was alert and interactive and sat when propped in a sitting position. However, his weight was 7600 g (5th percentile), and he was 65 cm long (10th percentile).
Dr. Nancy Lee Harris (Pathology): In addition to the topic of genetic counseling that this case raises, the child has important medical and surgical problems. Dr. Donahoe, could you describe the plan for management of the severe hypospadias?
Dr. Patricia K. Donahoe: The patient's phallus at birth measured 2.5 cm long (Figure 4). The phallus of a normal full-term newborn is 3.5 cm, plus or minus 0.5 cm. A penoscrotal urethral meatus was located at the base of the phallus. Each scrotum housed a testis of normal size. There was no evidence of retained mullerian structures either on physical examination or on ultrasonographic study. The patient's testosterone levels are low and will be further evaluated with human chorionic gonadotropin stimulation. The levels of mullerian-inhibiting substance and gonadotropin are normal. The infant will undergo a two-stage repair, with an expected good cosmetic and functional result by two years of age.
Figure 4. Hypospadias and Ambiguous Genitalia in the Patient at Eight Months of Age.
The patient's phallus at birth measured 2.5 cm, as calculated by adding two planes of measurements along the dorsum from the symphysis pubis to the distal tip. The diameter was 1 cm. A penoscrotal urethral meatus was located at the base of the phallus. Each scrotum housed a testis of normal size.
Final Diagnosis
Congenital abnormalities due to a chromosomal imbalance, karyotype 46,XY,rec(16)dup(16q)inv(16)(p13q22)pat, resulting from the recombination between the normal chromosome 16 and the inverted chromosome 16 in the patient's father.
Source Information
From the Departments of Medical Genetics (J.M.S.) and Pediatric Surgery (P.K.D.), Massachusetts General Hospital; the Department of Pathology, Brigham and Women's Hospital (N.T.L.); and the Departments of Pediatrics (J.M.S.), Pathology (N.T.L.), and Surgery (P.K.D.), Harvard Medical School — all in Boston.
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