American Journal of Medical Genetics 46574-578 (1993)

~~ ~ ~ ~~ ~~

Simpson-Golabi-Behmel Syndrome: Congenital Diaphragmatic Hernia and Radiologic Findings in Two Patients and Follow-Up of a Previously Reported Case Emily Chen, John P. Johnson, Victoria A. Cox, and Mahin Golabi Department of Pediatrics, Division of Genetics, University of California, Sun Francisco, California (E.C., V.A.C., M.G.); Children’s Hospital Oakland, Oakland, California (J.P. J.)

This report suggests the association of con- genital diaphragmatic hernia in Simpson- Golabi-Behmel syndrome by describing two unrelated males with this malformation. One male was the maternal half-nephew of our previously reported 8-year-old boy with this syndrome.

Review of the skeletal roentgenograms of these 2 affected males, and those of the previ- ously reported 8-year-old, documents flare of the iliac wings, narrow sacroiliac notches, and the presence of two carpal ossification centers as a newborn (‘‘advanced bone age”).

We also report the follow-up of the 8-year- old boy, now 16 years old, who continues to have significant overgrowth and speech, den- tal, developmental, and adjustment problems. 0 1993 Wiley-Lies, Inc.

KEY WORDS: overgrowth, iliac index, X-linked, skeletal roentgen- ograms

INTRODUCTION The Simpson-Golabi-Behmel (SGB) syndrome is an

X-linked recessive overgrowth condition associated with %oarse” facial appearance; hypertelorism; large mouth; short, upturned nose; hypoplastic nails [Simpson et al., 1975; Behmel et al., 1984; Opitz, 1984; Konig et al., 19911; and in some cases, midline brain defects, mental retardation, coccygeal skin tag and bony appendage, and other congenital anomalies [Tsukahara et al., 1984; Golabi and Rosen, 1984; Opitz et al., 1988; Neri et al., 19881. Gastrointestinal abnormalities such as pyloric

Received for publication November 16, 1992; revision received February 22, 1993.

Address reprint requests to Emily Chen, M.D., PhD, University of California, San Francisco, Box 0546, HSW 1429A, San Fran- cisco, CA 94143.

0 1993 Wiley-Liss, Inc.

stenosis, Meckel diverticulum, omphalocele, obstruc- tion, and incomplete rotation of the cecum have been described [Golabi and Rosen, 19841. One case of a con- genital diaphragmatic hernia was reported recently in a patient with SGB syndrome [Gurrieri et al., 19921. We report 2 additional patients with this finding and addi- tional abnormalities previously not described: a rup- tured cystic skin lesion probably initially a cystic hy- groma, small sciatic notches, flare of iliac wings (abnormally small iliac indices), and presence of carpal bones as a newborn.

CLINICAL REPORTS Patient 1 was the maternal half-nephew of the previ-

ously reported 8-year-old with SGB syndrome [Golabi and Rosen, 1.9841, and the 5th known affected male in this family. Patient 2 is an unrelated male with SGB syndrome.

PATIENT 1 The first patient was born to a 28-year-old G3P3 Pu-

erto Rican woman at 34-36 weeks gestation (Fig. 1). An elevated maternal serum alpha-fetoprotein level was discovered at 22 weeks of gestation. Fetal ultrasound study at 24 weeks showed a possible cystic hygroma, cystic ureterslkidneys, and a 1.5 cm cyst apparently in the chest. The karyotype was normal (46,XY) by amnio- centesis. There was no history of maternal diabetes. Rupture of membranes was premature by 2 weeks. De- livery was by caesarian section for breech presentation. Apgar scores were 3 and 5. The baby was foul-smelling and the mother had a fever. Birthweight was 2,965 g (> + 2 S.D.), length 47.5 cm ( + 1 S.D.), OFC 33.3 cm ( + 1 S.D.). A diaphragmatic hernia (the “cyst in the chest”) was noted at birth. The propositus also had an upswept forehead hair pattern with a left frontal whorl; frontal bossing; medial epicanthal folds; edematous eyelids; a flat nasal ridge; a broad, slightly beaked nose; mal- formed ears with bilateral presuricular dimples; and somewhat small, creased earlobes (Fig. 2). The neck was short and broad. An “ecchymotic” skin lesion, presum- ably the ruptured “cystic hygroma,” measured 7.2 x 6.4

Simpson-Golabi-Behmel Syndrome 575

II

111

I V

1 Fig. 1. Pedigree, Patient 1.

cm on the right shoulder (Fig. 3). The limbs were abnor- mal with broad hands and short, stubby fingers and hyperconvex nails, mild fifth finger clinodactyly, a sin- gle transverse crease on the left and prominent vertical creases, and broad feet with short toes. Cryptorchidism was also noted. Despite surgical correction of the dia- phragmatic hernia, the baby died at age 3 days of car- diorespiratory failure secondary to hypoplastic lungs, bronchopneumonia, and possible sepsis.

Autopsy showed a single-lobed, hypoplastic thymus, dysplastic and metaplastic mucosal epithelium of the larynx and trachea, cardiac situs solitus, atrial septal defect, preductal aortic coarctation, patent ductus ar- teriosus, right ventricular myocardial hypertrophy, pulmonary outflow tract stenosis associated with hy- pertrophic septal band, pulmonary interstitial emphy- sema, an intrapancreatic accessory spleen, lymphoid (lymph nodes, thymus, and spleen) atrophy, hydroneph- rosis, kydroureters, and bilateral peripheral cortical cystic renal dysplasia. Brain sections showed agenesis

Fig. 2. Patient 1.

Fig. 3. Skin lesion, probably a ruptured cystic hygroma, of Pa- tient l.

of the corpus callosum, with persistence of a bundle of Probst. A subarachnoid hemorrhage was found over- lying the cerebellum.

Review of radiographs documented left rib splaying, left cervical fusion, flare of iliac wings, (small iliac in- dices). Normally the mean of the iliac index, which is the sum of the acetabular angle and the iliac angle divided by 2, is about 80. In this case, the iliac index was less than 40; however, a pelvic radiograph with no tilt to the pelvis would be required for the exact measurements.

Patient 2 Patient 2 was born to a 32-year-old GP Caucasian

woman at 36V2 weeks gestation. The mother had poly- hydramnios beginning at 18 weeks of pregnancy. Glu- cose tolerance test was normal. Ultrasound showed a diaphragmatic hernia and polydactyly. Amniocentesis karyotype was normal (46,XY). Caesarian section was performed for breech presentation. Apgar scores were 5 and 7. About 7 minutes of CPR was required during the initial resuscitative period. Birthweight was 4.2 kg (>97%), length 58 cm (>97%), OFC 37 cm (98%). He had frontal bossing; “coarse” facial appearance; hypertelor- ism; a round, short nose; large mouth with a groove in the middle of the tongue and lower lip; tented upper lip (Fig. 4); high arched palate; a unilateral preauricular earpit (also seen in the father); a soft systolic murmur clinically consistent with peripheral pulmonic stenosis; unilateral postaxial polydactyly ; hypoconvex nails with complete absence of an index fingernail (Fig. 5); mild clinodactyly of the third toes; and cryptorchidism. He was on extracorporeal membranous oxygenation pre- and post-repair of the diaphragmatic hernia. Because of feeding problems and severe gastroesophageal reflux he

576 Chen et al.

Fig. 4. Patient 2.

required a Nissen fundoplication and gastrostomy tube placement. The etiology of a persistently elevated WBC count of 20,000 to 29,000 and an elevated platelet count that reached one million was unknown. Results of head ultrasound, echocardiogram, and hearing evaluation were normal. Abdominal ultrasound showed mega- nephric kidneys.

Radiographs from the neonatal period showed 13 slightly shortened ribs, flare of the iliac wings, small sciatic notches (Fig. 61, a bony protrusion of the lower medial aspect of the iliac bone (a spur), and the presence of two carpal bones (normally not present at birth).

Follow-up of Previous Case The previously described boy with Simpson-Golabi-

Behmel syndrome [Rosen and Golabi, 1984; patient 11 is now 16 years old. He is the only living affected SGB male in the family, depicted in generation I11 of Figure 1. He weighs over 80 kg and is 190 cm tall. He has a very “coarse” facial appearance, micrognathia (Fig. 7) and short fingers. He continues to have multiple problems.

Fig. 5. Hands of Patient 2. Note the postaxial polydactyly on the patient’s right hand, and complete absence of the index fingernail on

Fig. 6. Radiograph of Patient 2. Note diaphragmatic hernia, 13 ribs, flare of iliac wings, small sciatic notches.

He has had a lingual frenectomy and multiple dental procedures for severe dental crowding, gingivitis, bilat- eral crossbite, and overdevelopment of the posterior al- veolar processes of the maxilla. He requires speech ther- apy for limited upward tongue mobility, difficulty bringing his lips together, and a submucous cleft palate. In addition to the previously noted coloboma of the right disc, he was recently noted to have strabismus, an ex- cyclotorted macula of the right fundus, exotropia in pri- mary gaze, marked inferior oblique overaction, and probably congenital bilateral superior oblique palsies. He is in special education and has low self-esteem.

Review of radiographs from his neonatal period docu- mented a bell-shaped chest, 6 lumbar vertebrae, fusion of sacral vertebrae, posteriorly tilt of sacrum, mild flare of iliac wings, and two carpal ossification centers at birth.

DISCUSSION The SGB syndrome should be considered pre- and

postnatally in any male with a congenital diaphragma- tic hernia, especially if macrosomia is present. This

his left hand. syndrome, recently localized to chromosome Xqcen-q21

Simpson-Golabi-Behmel Syndrome 577

charidoses, Shwachman syndrome, hypophosphatasia, and caudal dysplasia sequence [Taybi and Kane, 1968; Taybi and Lachman, 19901. It has been suggested that these radiological findings may be found in conditions characterized by weakness of the abdominal muscula- ture. In our review of the published papers on F’ryns syndrome, these findings were also observed in one ra- diograph of a case with F’ryns syndrome [Bamforth et al., 19891.

Small sciatic notches have been described for some achondroplasia patients and other skeletal dysplasias [Taybi and Lachman, 19901. The SGB syndrome should be added to this list.

There are only a few conditions in which the presence of carpal bones in newborn infants has been noted: Larsen syndrome, spondylometaphyseal abnormality, Marshall-Smith syndrome, diastrophic dysplasia, and two overgrowth conditions: the Wiedemann-Beckwith and Weaver syndromes. The SGB syndrome is an addi- tional overgrowth condition where this finding can be observed.

We conclude that a congenital diaphragmatic hernia, a “cystic skin lesion” possibly representing a ruptured cystic hygroma, the presence of carpal bones in a new- born, small iliac notches, and a decreased iliac index may be manifestations in the SGB syndrome. A dia- phragmatic hernia and a cystic hygroma could be diag- nosed prenatally by ultrasound or alpha-fetoprotein screening. Any time a diaphragmatic hernia is diag- nosed prenatally, other congenital malformations should be searched for, and the diagnosis of SGB syndrome should be considered.

Fig. 7. Previously reported patient with SGB syndrome, now 16 years old.

[Hughes-Bernie et al., 19921, is associated with malfor- mations of nearly all organ systems, excessive growth, and an increased risk for certain tumors [Hughes-Ben- zie et al., 19921. We report on 2 additional patients with a congenital diaphragmatic hernia to make a total of 3 known SGB cases with this malformation.

The differential diagnosis for SGB syndrome includes Wiedemann-Beckwith syndrome, F’ryns syndrome, stor- age disorders, infant of a diabetic mother, and mosaic tetrasomy 12p (Pallister-Killian) syndrome. Fryns syn- drome usually presents with congenital diaphragmatic hernia [F’ryns et al., 1979; Cuniff et al., 19901, and some cases of mosaic tetrasomy 12p may also have this find- ing [Bergoffen et al., 19921. In our two cases, F’ryns syndrome was considered as a possible diagnosis origi- nally, however in the first case, the propositus was mac- rosomic and had a family history of a 3 generation X-linked disorder including 4 other males affected with SGB syndrome [Golabi and Rosen, 19841. In the second case, there were many specific findings more consistent and/or pathognomonic for SGB syndrome: polydactyly, nail aplasia of the index finger, 13 ribs. The mothers of both cases had mild phenotypic expression of the syn- drome: “coarse” facial features and prominent mandi- ble, and an abnormal index fingernail and sacral ap- pendage in one mother.

The radiologic findings in these two patients, and that of the affected 16-year-old boy, show small iliac indices. Small acetabular and iliac angles have previously been described in Down syndrome, achondroplasia, asphyx- iating thoracic dysplasia, chondroectodermal dysplasia (Ellis-van Creveld syndrome), Rubinstein-Taybi syn- drome, osteogenesis imperfecta, Brachmann de Lange syndrome, prune belly sequence, several mucopolysac-

ADDENDUM We have encountered yet another SGB family with

three affected males (sons of one SGB carrier mother), one with a right-sided diaphragmatic hernia. On fetal ultrasonography, this male was found to also have bilat- eral cleft lip, 2-vessel cord, and remnants of a cystic hygroma of the left side of the neck. The maternal serum alpha-fetoprotein was increased. He was electively aborted at 21 weeks gestation. A half-brother, stillborn at 7 months gestation, had unilateral polydactyly. The other half-brother, now 19 years old, was noted at birth to have an abnormal facial appearance. He was later evaluated for possible Wiedemann-Beckwith syndrome, and only recently was diagnosed as SGB syndrome after the birth of his half-brother with the diaphragmatic hernia. He had advanced bone age as a child. Currently, he is 200 cm tall, has “coarse” facial features, a sub- mucous cleft palate, bifid uvula, prominent jaw (he had major jaw reduction surgery), macroglossia, macro- stomia, speech and dental problems, and broad neck. He does not have mental retardation.

ACKNOWLEDGMENTS The authors wish to thank Dr. Hooshang Taybi for his

expert interpretations of the radiographs and review of the manuscript, and Dr. Creig Hoyt for his recent oph- thalmologic exam of the 16-year-old boy.

578 Chenet al.

REFERENCES Bamforth JS, Leonard CO, Chodirker BN, Chitayat D, Gritter HL,

Evans JA, Keena B, Pantqar T, Friedman JM, Hall J (1989): Con- genital diaphragmatic hernia, coarse facies, and acral hypoplasia: Fryns syndrome. Am J Med Genet 32:93-99.

Behmel A, Ploch E, Rosenkranz W (1984): A new X-linked dysplasia gigantism syndrome: identical with the Simpson dysplasia syn- drome? Hum Genet 67:409-13.

Bergoffen J , McDonald-McGinn DM, Ruchelli E, Ross AJ, Punnett H, Kirk JJ , Campbell TJ, Miller RC, Richkind KE, Zackai EH (1992): Diaphragmatic hernia: etiologic clue to tetrasomy 12p mosaicism- presenting feature in a series of patients with Pallister-Killian syndrome (tetrasomy 12p mosaicism). Abstract A5: 24th March of Dimes Clinical Genetics Conference on Clinical and Molecular Cy- togenetics of Developmental Disorders, Stanford University.

Cuniff C, Jones KL, Saal HM, Stern HJ (1990): F’ryns syndrome: an autosomal recessive disorder associated with craniofacial anoma- lies, diaphragmatic hernia, and distal digital hypoplasia. Pediatrics

Fryns JP, Moerman F, Goddeeris P, Bossuyt C, Vanden Berge H (1979): A new lethal syndrome with cloudy corneae, diaphragmatic defects and distal limb deformities. Hum Genet 50:65-70.

Golabi M, Rosen L (1984): A new X-linked mental retardation-over- growth syndrome. Am J Med Genet 17:345-8.

Gurrieri F, Cappa M, Neri G (1992): Further delineation of the Simp- sonBehme1 (SGB) syndrome. Am J Med Genet 44136-7.

85(4):499-504.

Hughes-Benzie RM, Hunter AGW, Allanson JE, Mackenzie AE (1992): Simpson-Golabi-Behmel syndrome associated with renal dysplasia and embryonal tumor: localization of the gene to Xqcen-q21. Am J Med Genet 43:428-35.

Konig R, f ichs S, Kern C, Langenbeck U (1991): Simpson-Golabi- Behmel syndrome with severe cardiac arrhythmias. Am J Med Genet 38:244-7.

Neri G, Marini R, Cappa M, Borrelli P, Opitz J M (1988): Simpson- Golabi-Behmel syndrome: an X-linked encephalo-tropho-schisis syndrome. Am J Med Genet 30987-99.

Opitz JM (1984): The Golabi-Rosen syndrome-report of second family. Am J Med Genet 17:359-66.

Opitz JM, Herrmann J , Gilbert EF, Matalon R (1988): Simpson-Golabi- Behmel syndrome: follow-up of the Michigan family. Am J Med Genet 30301-8.

Simpson JL, Landey S, New M, German J (1975): Apreviously unrecog- nized X-linked syndrome of dysmorphia. BD:OAS. XI(2):18-24.

Taybi H, Kane P (1968): Small acetabular and iliac angles and associ- ated diseases. Radio1 Clin North Am Vol. VI (2):215-21.

Taybi H, Lachman RS (1990): “Radiology of Syndromes, Metabolic Disorders, and Skeletal Dysplasias.” 3rd ed. Year Book Medical Publishers, pp 878, 884.

Tsukahara M, Tanaka S, Kajii T (1984): A Weaver-like syndrome in a Japanese boy. Clin Genet 25:73-8.