Case reports

urine is a major source of amniotic fluid AFP, urethralobstruction alone would result in a low amniotic AFPlevel, as in disorders associated with renal dysgenesis.The raised amniotic fluid and maternal serum AFP ismost probably caused by regurgitation of bile andgastric contents into the amniotic fluid due to intestinalatresia. Transudation of fetal serum as a result of thegross abdominal distension is unlikely. Inomphaloceles with exposure of blood vessels, easytransudation of fetal serum will result in increasedamniotic fluid AFP (Nevin and Armstrong, 1975;Weiss et al., 1976), but when the exomphalos iscovered with skin amniotic fluid AFP is normal.

Fortunately, in most instances where a high AFPlevel has been found in the absence of a neural tubedefect, the fetal abnormalities have been so serious asnot to compromise the validity of termination of thepregnancy because of the high AFP value.

N. C. NEVIN, A. RITCHIE, F. MCKEOWN, ANDG. ROBERTS

Departments ofMedical Genetics, ofMidwifery andGynaecology, and ofPathology, Institute of ClinicalScience, The Queen's University ofBelfast, and theDepartment ofBiochemistry, The Royal Victoria

Hospital, Belfast, Northern Ireland

References

Brock, D. J. H. (1976) a-fetoprotein and the prenatal diagnosis ofcentral nervous system disorders. Child's Brain, 2, 1-23.

Chemke, J., Miskin, A., Rav-Acha, Z., Porath, A., Sagiv, M., andKatz, Z. (1977). Prenatal diagnosis of Meckel syndrome: alpha-fetoprotein and beta-trace protein in amniotic fluid. ClinicalGenetics, 11,285-289.

Kjessler, B., Johansson, S. G. O., Sherman, M., Gustavson, K. H.,and Hultquist, G. (1975). Alphafetoprotein in antenatal diagnosisof congenital nephrosis. Lancet, 1,432-433.

Nevin, N. C., and Armstrong, M. J. (1975). Raised alpha-fetoprotein levels in amniotic fluid and materal serum in a tripletpregnancy in which one fetus had an omphalocele. BritishJournal ofObstetrics and Gynecology, 82, 826-828.

Seppala, M., Laes, E., and Harvo-Noponen, M. (1974). Elevatedamniotic fluid alpha-fetoprotein in congenital oesophageal atresia.Journal of Obstetrics and Gynaecology of the British Common-wealth, 81, 827-828.

Thom, H., Johnstone, F. D., Gibson, J. I., Scott, G. B., and Noble,D. W. (1977). Fetal proteinuria in diagnosis of congenitalnephrosis detected by raised alpha-fetoprotein in maternal serum.British Medical Journal, 1, 16-18.

Weinberg, A. G., Milunsky, A., and Harrod, M. J. (1975). Elevatedamniotic fluid alpha-fetoprotein and duodenal atresia, Lancet, 2,496.

Weiss, R. R., Maori, J. N., and Elligers, K. W. (1976). Origin ofammiotic fluid alpha-fetoprotein in normal and defective preg-nancies. Obstetrics and Gynecology, 47, 697-700.

Requests for reprints to Dr N. C. Nevin, Departmentof Medical Genetics, The Queen's University ofBelfast, Institute of Clinical Science, Grosvenor Road,Belfast BT12 6BJ.

Primary hypogonadism in theBorjeson-Forssman-Lehmannsyndrome

SUMMARY A 28-year-old man with mentalretardation and multiple congenital malfor-mations was found to have the classical featuresof Borjeson-Forssman-Lehmann syndrome. En-docrine evaluations showed primary hypogonad-ism as the underlying endocrine abnormalityrather than hypopituitarism as suggested inearlier reports.

Borjeson et al. (1962, 1963) described 3 related maleswith an X-linked recessive syndrome characterised byprofound mental retardation, microcephaly, peculiarfatty facies, and hypogonadism. Findings in anisolated case (Baar and Galindo, 1965) and in one ofthe original patients (Brun et al., 1973) suggestedhypopituitarism as the basic endocrine abnormality.We report here the clinical and endocrine findings in

an individual with this syndrome.

Case report

The patient is a 28-year-old man who has resided in aninstitution for the retarded since age 11. Informationon his past history is scanty as we have beenunsuccessful in reaching any of his relatives. Accord-ing to the records, there are no similar cases or mentalretardation in the family. He was born with a weight of2.6 kg to a 15-year-old primigravida. Bilateral inguinalherniorrhaphies were performed at age 3 months, butthe operative reports are not available. He satunsupported at 3 years of age, stood alone at 31 years,and walked at 4 years. By 4 years of age he wascapable of some speech, but this has remained limitedto the utterance of several phrases.When admitted to the institution at age 11 years, his

height was 127 cm (50th centile for 8 years) and hisweight, 27-4 kg, was 5th centile for age. Major motorseizures occurred three times in the next seven yearsand at age 18, sodium pentobarbitone was prescribedintermittently because of increased frequency ofseizures. Diphenylhydantoin, 32 mg oraily, t.i.d., wasstarted at age 20 and has been given regularly to thistime. Seizures have been adequately controlled sinceage 23 when primidone, 100 mg, ti.d. was added tothis therapeutic regimen.He has been admitted to hospital with cellulitis of

the lower., extremities on several occasions. Recurrentotitis media with bilateral tympanic membrane per-forations necessitated a tympanoplasty at age 23. His

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I:

Fig. 1 Patient at age 26 years.

IQ has been estimated repeatedly in the range of 10 to30.At age 28 his standing height, 138 cm (supine

length 141 cm), was at the 50th centile for a 10-year-old; his head circumference, 53.5 cm, was at the 3rdcentile for an adult. He had soft puffy cheeks, largenormally formed ears, bilateral palpebral ptosis,depressed nasal bridge, and synophrys. The meanpalpebral fissure length as measured from innercanthus to outer canthus was 2.65 cm according tothe method of Smith (1976). The mean palpebralfissure length over the age of 5 years is 2.5 cm. Heart,chest, and abdominal examinations were normal withthe exception of bilateral herniorrhaphy scars. Hisentire body was soft and flabby with a mild fattygynaecomastia. The skin had a velvety texture. Genuvalgum was present and his first and second toes werewide-spaced bilaterally while his hands appearednormal. The phallus was small measuring 2 cm inlength and the scrotum and inguinal canals weredevoid of testes by palpation. A few short, straight,faintly pigmented hairs were present on the monspubis.

Fig. 2 X-rayfilms ofright hand andforearm, at age 26, showing openepiphysial growth plates, shortenedmetacarpals andphalanges, anddiminished muscle mass.

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LABORATORY EVALUATION1All parameters of an automated SMA- 12 (TechniconCorporation, Terrytown, New York) serum chemicalanalyses were normal and a karyotype showed a 46XY chromosomal constitution. A propranolol-glucagon stimulation test of growth hormone secretionusing 20 mg/M2 of propranolol and 1 mg of glucagonproduced a normal increase in growth hormone to 17ng/ml (Ruanqwit et al., 1972).

Serum T4 was 7*5 pg/dl (normal 4.6 to 10*7 ug/dl)and resin T3 uptake was 10.6% (normal 10.0 to14.6%).A random morning cortisol was 10,ug/dl (normal 5

to 20 ,g/dl). A morning cortisol of 2 ,ug/dl followed an11 p.m. oral dose of 2 mg of dexamethasone showingthe expected suppression (Cryer, 1976).A random serum testosterone was 48 ng/dl (normal

adult male: 300-1200 ng/dl). Random morning andevening determinations of luteinising hormone were 7and 6 mIU/ml, respectively (normal less than 11mIU/ml). Random rnorning and evening folliclestimulating hormones (FSH) were 24 and 15 mIU/ml(normal 4 to 25 mIU/ml). A 3-hour constant infusionof luteinising hormone-releasing hormone (LH-RH)(Ayerst) by the method of Reiter et al. (1976) resultedin appropriate increases in LH and FSH but nocorresponding rise in plasma testosterone, as shownin the Table.An encephalogram done while the patient was on

primidone and diphenylhydantoin showed diffuse, lowvoltage slow waves with no focal or paroxysmalactivity. This was judged to be consistent with diffuseorganic brain disease.

RADIOLOGICAL STUDIESX-ray studies show pronounced retardation of fusionof the epiphysial growth plates. Some fusion in thephalanges of the hand has occurred giving a bone ageapproximating 16 years. The hands appear otherwisenormal. Pattern profile analysis (Poznanski et al.,1972) shows generalised shortening of all bones of thehands with predominant involvement of the phalanges.The long bones are thin and moderately under-

mineralised. There is slight bowing of the radius andmild coxa vara. Soft tissue shows poor musculardevelopment, especially in the lower extremities. Thepelvis is normal, with the exception of flared iliacwings.

Table Results ofLH-RH stimulation test

Time FSH (MIUImI) LH (MIU/ml) Testosterone (ng/dl)

0 3.9 12 401 hour 14 252hours 23 213 hours 22 29 34

'All determinations were performed at Patterson-Coleman Laboratory,Tampa, Fl, USA.

Fig. 3 Lateral x-rayfilm showing spinal kyphosis at thedorsal-lumbarjunction. The interspace at D12-Ll isnarrowed; the adjacent vertebrae are deformed and the ringapophyses are open.

The upper lumbar spine shows a kyphos deformity,narrowed D12-L5 interspace, and secondary deform-ity of these vertebrae. The ring apophyses of thevertebral bodies remain unfused.The skull is somewhat 'squared' in the lateral

configuration but otherwise normal. The sutures arewell seen and reflect retarded development. There arenumerous dental caries and the teeth are poorlydeveloped.

Discussiont

The pattern of abnormalities found in this patientclosely corresponds to that originally described byBorjeson et al. (1962, 1963) in 3 related men and laterby Baar and Galindo (1965) in an isolated case.Features present in all cases include: microcephaly,excessive facial fat, large ears, enlarged breasts,abundant abdominal fat, small phallus, genu valgum,minimal pubic hair, seizures, and severe mental

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retardation. After reviewing photographs of the othercases and examining our patient, we propose that lidptosis rather than narrow palpebral fissues is thecommon eye finding,

All cases described had short stature (averageheight 145-7 cm, range 136 to 156 cm). Testes weretiny in the 3 cases coming to necropsy, and clinicallyabsent in the 2 living persons. Necropsy showed asmall pituitary with normal cytology in 1 case, anormal pituitary in the second, and the pituitary wasnot mentioned in the third. The association of shortstature and hypogonandism with a small pituitarygland in 1 patient, and gonadotropin levels in the lowerlimits of normal, by bioassay, in 2 patients, led to theinterpretation that hypopituitarism was responsible forthe endocrine abnormalities (Brun et al., 1974).Endocrine studies in our patient, however, showednormal pituitary responses as indicated by normalthyroid function, normal adrenal-pituitary axis, andnormal growth hormone and gonadotropin secretion.Low testosterone levels in our case are in keeping withprimary hypogonadism. We find no evidence tosupport hypopituitarism as a necessary part of any ofthe described cases.

F. THOMAS WEBER, JAIME L. FRIAS,RICHARD L. JULIUS, AND ALVIN H. FELMAN

Department ofPediatrics, University ofFloridaCollege ofMedicine, Gainsville, Florida 32610

ReferencesBaar, H. S., and Galindo, J. (1965). The Borjeson-Forssman-

Lehmann syndrome. Journal of Mental Deficiency Research, 9,125-130.

Borjeson, M., Forssman, H., and Lehmann, 0. (1962). An X-linked,recessively inherited syndrome characterized by grave mentaldeficiency, epilepsy, and endocrine disorder. Acta MedicaScandinavica, 171, 13-21.

Borjeson, M., Forssman, H., and Lehmann, 0. (1963). Combinationof idiocy, epilepsy, hypogonadism, dwarfism, hypometabolismand morphologic peculiarities inherited as an X-linked recessivesyndrome. In Proceedings on the 2nd International Congress ofMental Retardation, Vienna, 1961, Part 1, pp. 188-192. Ed. OttoStur. Karger, Basel.

Brun, A., Borjeson, M., and Forssman, H. (1974). An inheritedsyndrome with mental deficiency and endocrine disorder. Apatho-anatomical study. Journal ofMental Deficiency Research,18(1), 317-325.

Cryer, P. E. (1976). Diagnostic Endocrinology, pp. 68-69. OxfordUniversity Press, New York.

Poznanski, A. K., Garn, S. M., Nagy, J. M., and Gall, J. C. (1972).Metacarpophalangeal pattern profiles in the evaluation of skeletalmalformations. Radiology, 104, 1-13.

Reiter, E. Root, A. W., and Duckett, G. E. (1976). The response ofpituitary gonadotropes to constant infusion of luteinizinghormone-releasing hormone in normal prepubertal and pubertalchildren and in children with abnormalities of sexual develop-ment. Journal of Clinical Endocrinology and Metabolism, 43,400-411.

Ruanqwit, U., Cavallo, A., Fisher, J. N., and Crigler, U. F., Jr.(1972). Propranolol enhancement of immunoreactive growthhormone response to glucagon in children. Pediatric Research, 6,350.

Smith, D. W. (1976). Recognizable Patterns of Human Malfor-mations, 2nd ed., 467, W. B. Saunders, Philadelphia.

Requests for reprints to Dr. F. Thomas Weber,Department of Pediatrics, University of FloridaCollege of Medicine, Gainesville, Florida 33610,U.S.A.

Waardenburg-like features withcataracts, small head size, jointabnormalities, hypogonadism,and osteosarcoma

SUMMARY A 32-year-old black man was obser-ved with osteosarcoma and multiple anomaliesincluding deafness, hypopigmentation, cataracts,small head size, hypogonadism, and restrictedjoint mobility. The birth defects may comprise anew syndrome or combination of syndromes, ofwhich the malig-nancy may be a part.

Case report

The patient was ascertained in June 1976, during anaetiological assessment of sarcoma patients on asurgical service.

Gestation, labour, and delivery were normal. Theparents were a 16-year-old gravida 1, para 0, blackwoman, and an unrelated 16-year-old black man.Birthweight was 2.4 kg, and an umbilical hernia andclubfeet were present. Motor and speech developmentwere delayed and at 2 years hearing was found to beimpaired. Educational efforts were not made until age12 when the patient was sent to a school forhandicapped children. Greying of hair began at 12years; beard growth began at about 18 years. Hecurrently lives at home, cares for his personal needs,and has held two manual jobs.The father's medical and family history were un-

available; the mother had no physical or hearingabnormalities. The only birth defect or pigmentaryanomaly among 3 maternal half sibs and othermaternal relatives was profound childhood deafness inan otherwise normal cousin. The maternal grand-mother had an ovarian granulosa cell tumour, and amaternal aunt had uterine leiomyomata.

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