case-a 23 day old with hypospadias & failure to thrive.pdf

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351;22

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Case 36-2004: A 23-Day-Old Infantwith Hypospadias and Failure to Thrive

Joan M. Stoler, M.D., Natalia T. Leach, Ph.D., and Patricia K. Donahoe, M.D.

From the Departments of Medical Genet-ics (J.M.S.) and Pediatric Surgery (P.K.D.),Massachusetts General Hospital; the De-partment of Pathology, Brigham and Wom-en’s Hospital (N.T.L.); and the Departmentsof Pediatrics (J.M.S.), Pathology (N.T.L.),and Surgery (P.K.D.), Harvard MedicalSchool — all in Boston.

N Engl J Med 2004;351:2319-26.

Copyright © 2004 Massachusetts Medical Society.

A 23-day-old male infant was admitted to this hospital because of difficulty feeding andfailure to thrive.

His weight at birth was 2580 g; he was 45 cm long, the product of an uncomplicat-ed, full-term pregnancy, and born by spontaneous vaginal delivery at another hospitalto a 23-year-old woman (gravida 2, para 1). An obstetrical ultrasonographic evaluationat 21 weeks’ gestation had shown no abnormalities. At delivery, the amniotic fluid wasstained with meconium and there was a nuchal cord. Apgar scores were 2 at one min-ute and 7 at five minutes. He was briefly intubated and suctioned, and continuous pos-itive airway pressure was administered. Physical examination disclosed severe hypo-spadias and ambiguous genitalia. The examination revealed no other abnormalities.An evaluation for sepsis was negative. An abdominal ultrasonographic study of the childshowed mild left hydronephrosis.

He was initially breast-fed without apparent difficulty, but by the end of the first weekof life he began to gag or vomit with attempts to feed, and his interest in feeding ap-peared to decrease. Bottle-feeding with formula was initiated at one week of life be-cause of his poor weight gain. He continued to have difficulty with feeding, and hada poor sucking reflex, frequent gagging, and nonprojectile emesis. With the institutionof small feedings of 1 oz (30 ml) every 45 minutes, he ultimately regained his birth weightat day 21 of life. However, just two days later his weight had fallen to 2495 g, and he wasadmitted 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 beenborn prematurely and had “slow digestion”; a maternal aunt had lost a pregnancy ateight months.

On admission, the infant weighed 2495 g. The temperature was 36.6°C, the pulse120 beats per minute, and the respiratory rate 36 breaths per minute; the oxygen satu-ration was 99 percent while he was breathing room air. He appeared alert but small andthin. The face appeared dysmorphic, with wide-set eyes and a flat nasal bridge. The pal-ate was intact and the frenulum was short. The penis was small, and there was severehypospadias. The remainder of the examination was normal.

presentation of case

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On neurologic examination, the infant wasaroused 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 hishead or open his eyes in response to noise. Hemoved all his extremities. His left leg was flexedmost of the time, and his left hand was fisted. Hehad good head control but had axial and appendic-ular hypotonia. The deep-tendon reflexes were3+ in the right arm and hand and left brachioradi-alis. The left patellar reflex was 3+ and both anklereflexes were 2+. There was no clonus, and Babin-ski’s reflex was positive bilaterally. An examinationof the infant’s sensory reflexes showed withdrawalof both legs in response to noxious stimuli, withmore reaction on the right than on the left. The re-sults of a complete blood count, the levels of elec-trolytes, the results of renal- and liver-functiontests, and the levels of serum lactate and ammoniawere all within normal ranges; the urinalysis andan analysis of the cerebrospinal fluid showed noabnormalities.

On the first two hospital days, the infant con-tinued to feed poorly. The formula was changed anda nasogastric tube was placed, and supplementalfeedings were added, to a total of 70 ml every threehours. An upper gastrointestinal series of radio-graphs showed no evidence of tracheoesophagealfistula, hiatal hernia, aspiration, or pyloric steno-sis. There was one episode of gastroesophageal re-flux up to the level of the mouth. An ultrasono-graphic study of the brain showed linear areas ofechogenicity in the lenticulostriate area of the rightthalamus.

On the second hospital day, a consultant fromthe department of medical genetics obtained fur-ther details of the history, which included the in-formation that the infant’s father had two mater-nal first cousins with “premature aging,” but thatthere was no family history of hypospadias or birthdefects. The consultant’s examination showed asmall, slender baby with decreased subcutaneousfat. He was 53 cm long; the circumference of thehead was 33.6 cm. He had a triangular face, widelyspaced eyes that slanted upward, a slightly longphiltrum, a tight frenulum, a thin upper lip, mildretrognathia, and an intact palate. There was severeperineal hypospadias and a small penis. The scro-tum was almost bifid, and both testes were palpa-ble. Clinodactyly of the fifth finger was present onboth hands. There was diffuse hypotonia. A softsystolic cardiac murmur, grade 2 of 6, was heard

at the left upper sternal border. An examination bya neuro-ophthalmologist disclosed no abnormali-ties of the eyes.

On the third hospital day, treatment with raniti-dine was begun and the formula was changed again.Also on that day, the oxygen saturation decreasedto between 70 and 80 percent during feedings andwhile sleeping, requiring the administration of oxy-gen with the blow-by technique. He thereafter re-fused all oral feedings and was fed only by the na-sogastric tube.

On the fourth hospital day, labored breathingwith retractions and stridor developed. A chest ra-diograph showed mild interstitial pulmonary ede-ma. The infant was transferred to the intensive careunit, where continuous positive airway pressure wasadministered. On the sixth day, he was weaned toblow-by oxygen. The nasogastric tube was repo-sitioned to the jejunum and continuous feedingswere begun. He had periods of apnea. A magneticresonance imaging (MRI) scan of the brain obtainedon the seventh day showed no congenital abnormal-ities, no hydrocephalus, and unremarkable thala-mi without calcification. He weighed 2580 g. Meto-clopramide was added to the patient’s treatment.

The results of a diagnostic test were received.

Dr. Joan M. Stoler:

This child had intrauterine growthretardation, minor facial dysmorphism, microceph-aly, and hypospadias. These facts guided our ap-proach 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 de-scription of a common pediatric problem,

1,2

whichis cited as the cause of 1 to 5 percent of pediatrichospital admissions.

3

The definitions of failure tothrive

2,4,5

include a weight that is less than the thirdpercentile for age and sex on more than one occa-sion, a weight that is less than 80 percent of theideal weight for the child’s age, a decrease of twoor more percentile lines on the growth chart, anda weight at two weeks of age that is 10 percent lessthan the birth weight or an inability to regain thebirth weight by three weeks of age.

The causes of failure to thrive are varied and in-clude medical, environmental, and social factors.Causes can be broadly categorized as prenatal orpostnatal. In this child, there was evidence of bothprenatal and postnatal problems, since he was small

differential diagnosis


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at birth and difficulty in feeding developed duringthe first week of life.

prenatal causes of failure to thrive

Premature birth, maternal factors (exposure to vari-ous drugs, alcohol consumption, cigarette smoking,illness, or malnutrition), chromosomal disorders,single-gene disorders, and genetically associatedshort stature may all result in low birth weight orin small size for gestational age in an infant whocontinues to have poor growth (Table 1). One im-portant example of maternal exposure is the use ofalcohol during the pregnancy. Consumption of al-cohol in large amounts by a pregnant woman cancause the fetal alcohol syndrome, but it can alsoproduce babies who are small for gestational agewithout the obvious facial features of fetal alcoholsyndrome. In fact, so-called moderate alcohol con-sumption (two drinks per day) can have marked ef-fects on fetal growth.

6,7

This potentially harmfulfactor is often overlooked, even when the exposureis known.

8

Maternal illnesses that affect fetal growth in-clude hypertension and infectious diseases, suchas rubella, cytomegalovirus, syphilis, and less com-monly, toxoplasmosis and herpes simplex virus.Typically, there will be signs in the baby such as hep-atosplenomegaly, cataracts, retinopathy, and micro-cephaly, as well as abnormal results of laboratorytests (hematologic abnormalities, abnormalities ofthe central nervous system, or hearing deficits). Inthis case, a thorough pregnancy history, whichincluded possible exposures such as alcohol con-sumption, use of medications, and illnesses duringthe pregnancy, revealed no exposures that shouldhave affected the infant.

Chromosomal abnormalities and single-genedisorders encompass a large group of disorderscausing intrauterine growth retardation, subsequentpoor growth, and often a characteristic pattern ofbirth defects and minor anomalies. Genetic andchromosomal causes are implicated in about 10percent of cases in which children are hospitalizedfor failure to thrive.

9

Chromosomal abnormali-ties are present in 50 percent of all spontaneouslyaborted fetuses,

10

in 0.2 percent of newborns,

11

and in approximately 3 to 8 percent of children withbirth defects.

12

The particular pattern of anomaliesmay give clues to the specific genetic abnormality.As for single-gene disorders, in the Online Mende-lian 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 heredi-tary illnesses in the family; a half-brother and bothparents were normal. However, the finding of mul-tiple congenital abnormalities in the infant strong-ly suggested a genetic defect.

postnatal causes of failure to thrive

Postnatal causes of failure to thrive can be subdi-vided according to whether the child’s primary prob-lem is inadequate energy intake, impaired abilityto make use of the intake, or increased energy de-mands (Table 2). Some conditions fit into morethan one of these categories. For example, childrenwith congenital heart disease have an impaired foodintake because of fatigue and also increased met-abolic demands. In this patient, the physical exam-ination and observation of feeding revealed thatthe muscles were hypotonic and his sucking abil-ity was poor. His muscle strength and level of alert-ness were normal. The problem was poor intakecompounded by vomiting after even small feed-ings, a pattern that suggests reflux.

Further testing in a case such as this depends onwhat the history, physical examination, and ob-servation have shown (Table 3). The results of thestate newborn screening tests should be obtained.Currently, the Massachusetts newborn screeningprogram tests for 7 metabolic disorders as well ascongenital hypothyroidism and hemoglobinopa-thies, with optional screening for 22 more diseas-es, including cystic fibrosis. The results of the new-born screening were negative in this infant.

the differential diagnosis in this case

After the initial evaluation, I thought that a genet-ic abnormality was the most likely cause of thischild’s problems. The differential diagnosis in-cluded a chromosomal abnormality, the Smith–

Table 1. Prenatal Causes of Failure to Thrive.

Complications of premature birth

Maternal exposures, such as substantial alcohol use

Maternal illness: rubella, cytomegalovirus, syphilis, toxo-plasmosis, or herpes simplex virus

Maternal malnutrition

Chromosomal disorders

Single-gene disorders

Genetically associated short stature


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Lemli–Opitz syndrome, and the Opitz G/BBB syn-drome, also called the hypertelorism–hypospadiassyndrome.

Children with the Smith–Lemli–Opitz syndrome

typically have failure to thrive, genital abnormali-ties (in males), microcephaly, syndactyly of the sec-ond and third toes, and polydactyly. They have aparticular facial appearance that includes epican-thal folds, posteriorly rotated ears, ptosis, a smallpug nose, a broad alveolar ridge, and microgna-thia.

13-15

This syndrome is an autosomal reces-sive condition due to a deficiency of 7-dehydro-cholesterol reductase, with the resultant increasein 7-dehydrocholesterol, a precursor to cholester-ol. The gene is called

DHCR7,

and it is located onchromosome 11. The Smith–Lemli–Opitz syndromeis not uncommon, with an incidence of 1 in 20,000to 1 in 40,000 among people of European ances-try.

16

The diagnosis is determined by a measure-ment of the levels of serum 7-dehydrocholesterol.This child did not have the characteristic facial fea-tures or findings in the extremities.

The hypertelorism–hypospadias syndrome con-sists of hypertelorism; upward-slanting palpebralfissures with epicanthal folds; a broad, flat nasalbridge; a cleft lip with or without a cleft palate; andmale genital abnormalities that can include hypo-spadias, cryptorchidism, a bifid scrotum, and initialfailure to thrive.

17,18

The failure to thrive is causedby swallowing difficulties, with recurrent aspirationdue to anomalies of the larynx and of the epiglottisor the trachea or both — most notably laryngotra-cheal clefts. There are two types of the hypertelo-rism–hypospadias syndrome, an X-linked form andan autosomal dominant form linked to chromoso-mal locus 22q11.2. This baby had hypertelorism,genital abnormalities, and failure to thrive that wasdue to poor food intake. However, he did not havea cleft lip and was not known to have a laryngeal ortracheal abnormality.

Genetic testing was recommended, includinga karyotype analysis, fluorescence in situ hybridi-zation (FISH) to look for the deletion at 22q11.2,and measurement of the serum level of 7-dehydro-cholesterol. The results of FISH and the 7-dehydro-cholesterol level were within normal limits.

Dr. Natalia T. Leach:

The chromosomal analysis ofthe patient’s peripheral-blood lymphocytes revealeda structurally abnormal chromosome 16, with addi-tional material of unknown origin on the distal partof the p (short) arm in every metaphase analyzed(Fig. 1A). A karyotype of 46,XY,add(16)(p13) wasinitially assigned, and an analysis of parental chro-

pathological discussion

Table 2. Postnatal Causes of Failure to Thrive.

Mechanism Underlying Cause Example

Inadequate energy intake

Mechanical feeding problems

Breathing difficultiesPoor suck and swallow

reflexPoor appetiteEasy fatigabilityChronic vomiting

Cleft lip, cleft palateChoanal atresiaNeuromuscular disordersAnemia, chronic infectionsCongenital heart diseaseGastroesophageal reflux

Poor absorption or use of absorbed nutrients

Malabsorption syn-dromes with lack of pancreatic en-zymes or inade-quate substrate for absorption

Conditions with nutri-ent loss

Cystic fibrosisShort-gut syndromeChronic liver or renal

diseaseChronic diarrhea

Increased metabolic demands

Conditions that have increased energy requirements

Congenital heart diseaseBronchopulmonary

dysplasiaHyperthyroidismRenal failureNeoplasmsInfectious or inflammato-

ry processes

Table 3. Laboratory Evaluation of Failure to Thrive.

Initial screening testsComplete blood countLevels of electrolytes, urea nitrogen, creatinineUrinalysisUrine cultureLiver-function tests to measure levels of protein,

albuminState newborn screening

Specialized testsThyroid-function testsStool analysisSweat testTest for human immunodeficiency virusKaryotype analysisLevels of amino acidsLevels of organic acids

Imaging studiesUpper gastrointestinal seriesRenal ultrasonographyComputed tomographic scan or MRI of the brainEchocardiography


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mosomes was requested to determine whether theabnormal chromosome was new or familial.

After the findings had been reported to theparents, the baby’s father stated that he and sever-al members of his family had an abnormality ofchromosome 16. It was also learned that the pa-tient’s mother had sought prenatal counseling withDr. 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 themother was asked why she had not returned for ge-netic testing, she replied that she had not wanted tohave to think about the possibility of ending thepregnancy.

The genetics team then discovered that thisfamily had been extensively studied 20 years previ-ously by our laboratory.

19

The patient’s father hadbeen karyotyped at two years of age, and a pericen-tric inversion of chromosome 16, with breakpointsin bands p13 and q22 (the inverted segment in-cludes the centromere), had been found with theuse of quinacrine and Giemsa (GTG banding) (Fig.1C and 1D). (Giemsa and fluorescent dye quinacrineare DNA-binding agents that produce chromosome-specific banding patterns used for chromosomalanalysis.) Therefore, the final karyotype of the in-fant was reported as 46,XY,rec(16)dup(16q)inv-(16)(p13q22)pat. The nomenclature reflects the factthat the abnormal chromosome 16 arose as a resultof a recombination between the normal and the in-verted chromosome 16 in the patient’s father.

Balanced inversions can have clinical conse-quences if the chromosomal breakpoints eitherdisrupt a gene or separate it (or a group of genes)from a regulatory element. Neither scenario ap-pears to apply to this particular inversion of chro-mosome 16, because of the normal phenotype inthe patient’s father and in the other carriers in thisfamily. The primary concern with respect to the car-riers is the risk of having chromosomally abnor-mal offspring because of the production of unbal-anced gametes. This occurs as a result of an unevennumber of recombination events between the nor-mal and inverted chromosomes, within the invert-ed region.

During chromosome pairing in meiosis, a loopis formed in the chromosomal region that is in-volved in an inversion, to allow for optimal align-ment of the inverted chromosome and its normal

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 chromo-some 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).

D

A

C

Normal chromosome 16 inv(16)(p13q22)B

1 2 3 4 5

6 7 8 9 11 1210

13 14 15

p13

16 17 18

19 20 21 22 X Y

16 inv(16) 16 inv(16)

q22


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homologue (Fig. 2). For example, a single crossing-over event within the inversion loop would resultin four different gametes: one with a normal chro-mosome, another with an inverted chromosome,and two with different recombinant chromosomeswith partial duplications (producing partial triso-my in the offspring) and deletions (producing par-tial monosomy in the offspring). The risk of hav-ing an abnormal offspring depends on the size andtype of inversion. Large pericentric inversions havea higher likelihood of recombination and a great-er risk of producing viable recombinant offspringbecause a smaller genetic imbalance is created.

20

In the study of the father’s family, karyotypeanalyses of members of three generations wereperformed

19

(Fig. 3). Multiple carriers of the inver-sion of chromosome 16, as well as carriers of therecombinant chromosome 16, were identified, in-cluding two people with cytogenetically identifiedrecombinant chromosome 16: an infant girl withcongenital heart disease and pulmonary hypoplasia,who died at six hours of age, and an aborted malefetus, with massive hydrocephalus and a single um-bilical artery (who was a sibling to the father of theinfant in this case). Recombinant chromosome 16,in association with multiple anomalies, was sus-pected in two other deceased family members.

Although the GTG-banded appearance of therecombinant chromosome 16 in the two patientsdescribed by Bianchi et al.

19

and of that in this in-fant appear to be identical, molecular character-ization of the recombinant chromosome 16 in thestudy by Bianchi et al. showed differences in thebreakpoint regions. This may explain the variationin the clinical phenotype among patients with re-combinant chromosome 16. A cytogenetically iden-tical inv(16)(p13q22) is found in some cases ofacute myeloid leukemia as an acquired abnormali-ty. However, the delineation of the breakpoints ofthis familial chromosome 16 inversion showed thatthis constitutional rearrangement has distinctly dif-ferent breakpoints from the inversion found inacute myeloid leukemia.

21

A number of patients with the chromosomal im-balances known as partial trisomy 16 and partialmonosomy 16 have been described in the literature,each having a number of clinical features that over-lap those of our patient with the recombinant chro-mosome 16 and with the other patients with the re-

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 al-low for optimal alignment of the inverted chromosome and its normal homo-logue, 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 par-tial trisomy in the offspring) and deletions (producing partial monosomy in the offspring).

XX

nl

1

1

6

5

5

4

4

3

32

2

6

2

3

4

5

6

11

2

3

4

5

1

6

2

3

4

5

6

1

5

4

3

2

6

rec rec inv

Figure 3. Pedigree of the Patient’s Father.

The patient is designated by the arrow. The infants who had multiple birth de-fects 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 per-sons 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 fe-male family members, and the diagonal lines family members who have died.White circles or squares indicate family members who do not have the inver-sion, and triangles a spontaneous miscarriage.

? ?

?


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combinant chromosome described in the study ofthis family. However, a strict comparison betweenthese groups of patients is hindered by the fact thatpartial trisomy or monosomy 16 is usually accom-panied by partial trisomy or monosomy of otherchromosomes.

Dr. Stoler:

The first article published on this familystated that “in the family described here, there areat least 6 young children in generation III who carrythe inv(16). They are all at risk for developing ab-normal recombinants in their gametes. Althoughnone of the individuals has yet reached reproduc-tive age, we have met with all of their parents to pro-vide genetic counseling. As tragically demonstratedin this family, prenatal diagnosis should be of-fered to any individual known to carry inv(16).”

19

Despite this, the father of this baby did not fullycomprehend the implications. He had assumed thatsince he himself did not have any medical problemsand since his brother, also a carrier of the inv(16)mutation, had two normal children, the mutationdid not pose a substantial risk. He also was un-aware that his mother had terminated a pregnancyas reported in the family study

19

(Fig. 3). This casedemonstrates that information may not be con-veyed accurately within families and raises the is-sue of how we can better convey this information.

Poor feeding and lack of weight gain have con-tinued to be problems for this child. When he wasthree months of age, a gastrostomy tube was placed,after which the patient had continuous vomitingwith large-volume feedings; one month later a lap-aroscopic Nissen fundoplication was performed.His reflux resolved and he is now able to toleratefull feedings through his gastrostomy tube.

At an examination at the age of eight months,he showed some developmental progress. He wasalert and interactive and sat when propped in a sit-ting position. However, his weight was 7600 g (5thpercentile), and he was 65 cm long (10th percentile).

Dr. Nancy Lee Harris

(Pathology): In addition tothe topic of genetic counseling that this case raises,

the child has important medical and surgical prob-lems. Dr. Donahoe, could you describe the plan formanagement of the severe hypospadias?

Dr. Patricia K. Donahoe:

The patient’s phallus atbirth measured 2.5 cm long (Fig. 4). The phallus ofa normal full-term newborn is 3.5 cm, plus or minus0.5 cm. A penoscrotal urethral meatus was locatedat the base of the phallus. Each scrotum housed atestis of normal size. There was no evidence of re-tained mullerian structures either on physical exam-ination or on ultrasonographic study. The patient’stestosterone levels are low and will be further eval-uated with human chorionic gonadotropin stimula-tion. The levels of mullerian-inhibiting substanceand gonadotropin are normal. The infant will un-dergo a two-stage repair, with an expected goodcosmetic and functional result by two years of age.

Congenital abnormalities due to a chromosomalimbalance, karyotype 46,XY,rec(16)dup(16q)inv-(16)(p13q22)pat, resulting from the recombinationbetween the normal chromosome 16 and the in-verted chromosome 16 in the patient’s father.

discussion of management

final diagnosis

references

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Marcovitch H. Failure to thrive. BMJ1994;308:35-8.

2.

Kirkland RT. Failure to thrive. In: Mc-Millan JA, DeAngelis CA, Feigin RD, War-chaw JB, eds. Oski’s pediatrics: principlesand practice. 3rd ed. Philadelphia: Lippin-cott-Raven, 1999:752-5.

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Olsen EM, Johannsen TH, Moltesen B,Skovgaard AM. Failure to thrive among hos-pitalized 0-2 year-old children. Ugeskr Lae-ger 2002;164:5654-8. (In Danish.)

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Wilcox WD, Nieburg P, Miller DS. Fail-ure to thrive: a continuing problem of defi-nition. Clin Pediatr (Phila) 1989;28:391-4.

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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 calcu-lated 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.


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Robin NH, Feldman GJ, Aronson AL, etal. Opitz syndrome is genetically heteroge-

neous, with one locus on Xp22, and a secondlocus on 22q11.2. Nat Genet 1995;11:459-61.

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Gonzales CH, Herrmann J, Opitz JM.The hypertelorism-hypospadias (BBB) syn-drome. Eur J Pediatr 1977;125:1-13.

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Bianchi DW, Nicholls RD, Russell KA,Miller WA, Ellin M, Lage JM. Pericentric inver-sion of chromosome 16 in a large kindred:spectrum of morbidity and mortality in off-spring. Am J Med Genet 1992;43:791-5.

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Gardner RJM, Sutherland GR. Chromo-some abnormalities and genetic counsel-ing. New York: Oxford University Press, 1996:137-50.

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Stallings RL, Bianchi DW. FISH map-ping of a human chromosome 16 constitu-tional pericentric inversion inv(16)(p13q22)found in a large kindred. Am J Med Genet1994;52:346-8.

Copyright © 2004 Massachusetts Medical Society.

35-millimeter slides for the case records

Any reader of the

Journal

who uses the Case Records of the Massachusetts General Hospital as a medical teaching exercise or reference material is eligible to receive 35-mm slides, with identifying legends, of the pertinent x-ray films, electrocardiograms, gross specimens, and photomicrographs of each case. The slides are 2 in. by 2 in., for use with a standard 35-mm projector. These slides, which illustrate the current cases in the

Journal,

are mailed from the Department of Pathology to correspond to the week of publication and may be retained by the subscriber. Each year approximately 250 slides from 40 cases are sent to each subscriber. The cost of the subscription is $450 per year. Application forms for the current subscription year, which began in January, may be obtained from Lantern Slides Service, Department of Pathology, Massachusetts General Hospital, Boston, MA 02114 (telephone 617-726-2974).

Slides from individual cases may be obtained at a cost of $35 per case.


case-a 23 day old with hypospadias & failure to thrive.pdf

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