Simpson-Golabi-Behmel Syndrome, Type 1

A number sign (#) is used with this entry because of evidence that the Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is caused by mutation in the gene encoding glypican-3 (GPC3; 300037) on chromosome Xq26.

Some evidence suggests that disruption of the GPC4 gene (300168), which is adjacent to the GPC3 gene, may also cause the disorder (see MOLECULAR GENETICS).

Description

Simpson-Golabi-Behmel syndrome is an X-linked condition characterized by pre- and postnatal overgrowth, coarse facies, congenital heart defects, and other congenital abnormalities (Xuan et al., 1999). It shows phenotypic similarities to Beckwith-Wiedemann syndrome (BWS; 130650), another overgrowth syndrome.

See also Simpson-Golabi-Behmel syndrome type 2 (SGBS2; 300209), which has been associated with a mutation in the CXORF5 gene (300170) on chromosome Xp22.

Clinical Features

Simpson et al. (1975) reported 2 male first cousins, sons of sisters, who had a distinctive facial appearance, including a large protruding jaw, widened nasal bridge, upturned nasal tip, and enlarged tongue. Other features included broad stocky appearance and broad, short hands and fingers. One of the patients had clefting of the lower lip. Intelligence was normal. The family referred to the appearance as 'bulldog'-like. Laboratory tests excluded hypothyroidism. Close linkage with the Xg blood group locus was excluded.

Kaariainen (1981) observed a tall (192 cm) 40-year-old man with operated pectus excavatum, ventricular septal defect, central cleft of the lower lip, peculiar cup-shaped ears with knobbiness and nodularity, short clubbed terminal phalanges, low-pitched voice, and cataracts developing at age 35. The parents, who came from different parts of Finland, were 170 and 160 cm tall. A brother, height 180 cm, died at age 18 years of ventricular septal defect and pulmonary hypertension. He looked like the surviving brother and quite different from other members of the family. Kaariainen (1982) concluded that the disorder was the same as that described by Simpson et al. (1975).

Golabi and Rosen (1984) reported a family in which 4 males in 4 sibships spanning 3 generations connected through females had prenatal and postnatal overgrowth; short, broad, upturned nose; large mouth, midline groove of tongue, inferior alveolar ridge and lower lip; submucous cleft palate; 13 ribs; Meckel diverticulum; intestinal malrotation; coccygeal skin tag and bony appendage; hypoplastic index fingernails; unilateral postaxial polydactyly; and bilateral syndactyly of fingers 2 and 3. Mental retardation was also a feature. The carrier mother of the propositus had a large mouth, coccygeal skin tag and bony appendage, and hypoplastic index fingernails. Behmel et al. (1988) suggested that the mental retardation in the family reported by Golabi and Rosen (1984) may have had a basis unrelated to the rest of the syndrome. Intelligence in the dysplasia gigantism syndrome is usually normal or only mildly retarded. Chen et al. (1993) reported the birth of a fifth affected male in the family reported by Golabi and Rosen (1984) and provided a follow-up of a patient who was 8 years old at the time of the initial report. He was 190 cm tall, had coarse facial features, micrognathia, short fingers, and dental abnormalities. Problems with speech and psychosocial development were also described. The newborn member of the family and a second unrelated male with this syndrome were found to have congenital diaphragmatic hernia. On the basis of these cases, Chen et al. (1993) noted that radiologic findings include flaring of the iliac wings, narrow sacroiliac notches, and the presence of 2 carpal ossification centers as a newborn ('advanced bone age').

In a pedigree pattern consistent with X-linked recessive inheritance, Behmel et al. (1984) observed 11 male newborns with a syndrome similar to that described by Simpson et al. (1975): elevated birth weight and length; disproportionately large head with coarse, distinctive facies; short neck; slight obesity; and broad, short hands and feet. The affected males who reached adulthood attained heights of about 2 m; their unusual facial and general appearance and clumsiness, remarkable during infancy and childhood, became somewhat less conspicuous. In all but 1, intelligence was normal, as it was in the 2 cases of Simpson et al. (1975). Behmel et al. (1988) provided follow-up on the family reported by Behmel et al. (1984) and added a second Austrian family. They concluded on the basis of these studies that the syndrome was identical to that reported by Simpson et al. (1975) and Golabi and Rosen (1984).

Opitz (1984) reported a family in which 3 boys born to half sisters were affected. The nose in affected males was particularly similar to that in the patients of Golabi and Rosen (1984). Opitz et al. (1988) provided follow-up of 1 of the patients reported by Opitz (1984). He died at age 25 months without attaining any psychomotor development and with a neurologic picture of irritability, hypotonia, seizures, deafness, and possible cortical blindness. Autopsy showed spongiform degeneration of brainstem and cerebrum; this patient may have had a different disorder.

Kajii and Tsukahara (1984) reported a possible case, which was originally described by Tsukahara et al. (1984) as 'a Weaver-like syndrome.' Garganta et al. (1988) and Garganta and Bodurtha (1992) concluded on the basis of 2 affected brothers with overgrowth, macrocephaly, polydactyly, supernumerary nipples, and a characteristic facial appearance that mental retardation is not a consistent feature. One of the boys had pulmonic stenosis and cleft palate. One of the boys also had creases of the posterior helix, suggesting the Beckwith-Wiedemann syndrome. Garganta et al. (1988) suggested that the Simpson dysmorphia syndrome and Golabi-Rosen syndrome are the same disorder. Neri et al. (1988) reported an affected kindred. They commented on the high frequency of infant death, a finding noted by others, and stated that postaxial hexadactyly of the hands is an occasional feature. They suggested the designation 'Simpson-Golabi-Behmel syndrome.' An affected patient reported by Gurrieri et al. (1992) also had postaxial polydactyly and extra nipples.

Hughes-Benzie et al. (1992) reported a family with 6 affected males in 5 sibships in 3 generations. All had pre- and postnatal overgrowth, with 2 adult males attaining heights over 195 cm. Other features included coarse facies with hypertelorism, broad nasal root, cleft palate, full lips with a midline groove in the lower lip, grooved tongue with tongue tie, prominent mandible, congenital heart defects, arrhythmias, supernumerary nipples, splenomegaly, large dysplastic kidneys, cryptorchidism, hypospadias, and postaxial hexadactyly. All affected individuals were of normal intelligence. One affected male died at age 19 months of a neuroblastoma. Eight carriers who showed varying manifestations of the syndrome were identified.

Ireland et al. (1993) presented a 5-generation family. Overgrowth was present in 4 affected males and 3 out of 4 carrier females. The facial features in affected males included facial asymmetry with hypertelorism and upward slanting palpebral fissures. In addition, they had a broad nose, thin lips, and a prominent mandible. The palate was high-arched, the tongue was grooved and tethered with an anterior notch, and there was a groove in the lower lip. None of the affected males was mentally retarded. One of the affected males had bilateral hydronephrosis and a nonfunctioning kidney; another had bilateral cataracts diagnosed at age 2 years and retinal detachment at age 5 years. Facial features in carrier females included short, narrow palpebral fissures, upturned nasal tip with a prominent columella, and a prominent chin. Both affected males and carrier females showed extra lumbar and thoracic vertebrae and accessory nipples.

From a review of reported cases, Garganta and Bodurtha (1992) concluded that early perinatal and infant mortality is high in patients with SGBS. Terespolsky et al. (1995) commented on the wide clinical range in reported cases of SGBS, ranging from a mild form associated with long-term survival to an early lethal form with multiple congenital anomalies and severe mental retardation. They found 8 reported families in which affected individuals died in infancy.

Konig et al. (1991) suggested that cardiac arrhythmias may be a major component of the SGB syndrome and can be responsible for death in early infancy and perhaps for cardiac arrest in the adult. Lin et al. (1999) concluded that cardiac abnormalities of any type are common in SGBS, occurring perhaps in almost one-half of cases, with cardiovascular malformations seen in one-third of cases.

Neri et al. (1998) reviewed the clinical and molecular aspects of SGBS. They emphasized that an increased risk of neoplasia in SGBS must be kept in mind, especially in young patients. They stated that Wilms tumor of the kidney had been found in several members of affected families in Canada (Hughes-Benzie et al., 1992; Xuan et al., 1994).

Kim et al. (1999) reported choledochal cysts in SGB syndrome. The patient was a new member of a family with this disorder previously reported by Chen et al. (1993) and Golabi and Rosen (1984). The diagnosis of SGBS had been suspected prenatally because of the family history and prenatal ultrasound findings of polyhydramnios, macrosomia, double-bubble sign suggestive of duodenal atresia, bilateral clubfoot, and visualization of a penis indicating male gender. At birth the length was 55 cm (97%). He had a coarse facial appearance, vertical furrows between the eyebrows, increased interpupillary distance, bifid uvula but no cleft lip or palate, and macrostomia. He had low-set, large floppy ears. The choledochal cyst was discovered at operation for other intraabdominal anomalies. Kim et al. (1999) provided an updated pedigree of the family with 7 affected individuals in 3 generations.

Griffith et al. (2009) reported 3 brothers with SGBS, aged 20 months, 4 years, and 6 years, all of whom had cryptorchidism. The eldest brother also had chordee of the penis, penoscrotal hypospadias, and penoscrotal transposition requiring multiple surgeries. The authors stated that this was the first SGBS patient with such anomalies to survive beyond the neonatal period, and suggested that a range of genital anomalies should be considered a nonrandom feature of SGBS.

Other Features

Cureton et al. (2007) described a 2-year-old boy with SGBS who presented with a hepatic lesion, which upon resection was found to be a vascular malformation. The authors suggested that, in addition to developing visceral solid malignancies, SGBS patients may also be at risk for developing vascular malformations.

Penisson-Besnier et al. (2008) reported a 44-year-old man with classic SGBS, confirmed by genetic analysis (300037.0011), who presented with acute internal carotid artery dissection. Radiography showed arterial redundancies of the affected artery. The authors postulated that the overgrowth involved in SGBS may have caused an increase in the length of the carotid, leading to coiling and thus to a greater risk of dissection.

Inheritance

Simpson-Golabi-Behmel syndrome typically shows X-linked recessive inheritance. However, some female mutation carriers may show mild features, presumably due to skewed X-chromosome inactivation. Yano et al. (2011) reported a Jordanian family in which 3 sibs, a boy and a dizygotic twin boy and girl pair, had SGBS due to a truncating mutation in the GPC3 gene inherited from their mother, who had very subtle features of the disorder. The 2 boys had the classic disorder, including overgrowth, coarse facies, macroglossia, pectus excavatum, and developmental delay, whereas the girl had milder but suggestive features, such as developmental delay, macrocephaly, patent ductus arteriosus, and diaphragmatic hernia. The mother had normal intelligence and very mild signs, such as slight coarse facies and macrostomia. X-inactivation studies of blood, which is of mesodermal origin and appropriately reflects GPC3 expression, showed that the affected daughter had a wildtype:mutant ratio of 20-29:71-80 favoring expression of the mutant allele, whereas the mother had a 57:43 ratio with slight favoring of the normal allele. X-inactivation ratios were different in other tissues. Overall, the results provided an explanation for the different phenotypic manifestations of SGBS in the 2 female mutation carriers in this family.

Diagnosis

Differential Diagnosis

Hughes-Benzie et al. (1992) drew attention to the superficial similarities in the appearance of pedigrees segregating in an X-linked recessive pattern and those exhibiting an autosomal dominant pattern with imprinting of specific genes. As an illustration of the confusion, they referred to a family misdiagnosed as having Beckwith-Wiedemann syndrome, who was found to have SGBS based on clinical findings of postaxial polydactyly, midline groove in the lower lip, and more severely affected males (Niikawa et al., 1986; case 4). Shared clinical features of BWS and SGBS include macrosomia, macroglossia, cleft palate, visceromegaly, earlobe creases, hernias, neonatal hypoglycemia, and a risk of embryonal tumors.

Xuan et al. (1994) pointed to the report by Punnett et al. (1974) of a female with a putative diagnosis of Beckwith-Wiedemann syndrome and a balanced reciprocal (X;1)(q26;q12) translocation. Xuan et al. (1994) suggested that the description of the young woman was entirely compatible with SGBS and that the translocation may have disrupted the SGBS gene. Punnett (1994) reexamined this 23-year-old patient who, in addition to typical manifestations, had diaphragmatic hernia and pulmonic valve stenosis, and concluded that she actually had SGBS.

Verloes et al. (1995) commented on the difficulties in the differential diagnosis of overgrowth syndromes in the neonatal period and the phenotypic overlap of BWS, SGB syndrome, and Perlman syndrome (267000). They suggested that it may be necessary to add genital ambiguity, hydramnios, and nephroblastomatosis to the clinical spectrum of Simpson-Golabi-Behmel syndrome and to keep in mind a possible risk for embryonal tumors in patients with this syndrome.

Gertsch et al. (2010) reported a male infant initially diagnosed with Timothy syndrome (601005) after birth on the basis of QT interval prolongation in the neonatal period and syndactyly. At day 7 of life, the patient received an implantable cardioverter-defibrillator (ICD). However, genetic testing did not identify a mutation in the CACNA1C gene (114205), thus excluding a diagnosis of Timothy syndrome. Reevaluation of the patient showed that the syndactyly was postaxial and with bony fusion, not consistent with that observed in Timothy syndrome. Repeat genetic testing identified a truncating mutation in the GPC3 gene, confirming the diagnosis of SGBS. Other features in this infant included prenatal nuchal translucency on fetal imaging, high alpha-fetoprotein levels in the mother during pregnancy, macrosomia, hypoplastic index fingers, submucosal cleft palate, bifid uvula, and coarse facial features. The mother, who also carried the mutation, had tall stature, dolichocephaly, high-arched palate, pectus excavatum, joint laxity, and nonspecific T-wave abnormalities on EKG. The patient was found to have a normal QT interval at age 9 months, and the ICD was removed. Gertsch et al. (2010) emphasized the importance of distinguishing between Timothy syndrome and SGBS, since the former has a high incidence of neonatal mortality. They also noted that transient QT prolongation had not been reported in SGBS.

Mapping

By linkage analysis in a large family segregating SGBS, Hughes-Benzie et al. (1992) found linkage to chromosome Xcen-q21.3 (maximum lod score of 2.81 at marker DXYS68.)

Ireland et al. (1993) presented preliminary data supporting linkage of SGBS to Xqcen-q22 markers. In more extensive linkage analyses of the family reported by Ireland et al. (1993), Xuan et al. (1994) mapped the putative SGBS locus to Xq26; the closest linkage was to HPRT (308000) with a maximum lod score of 7.45 at theta = 0.00. Recombinations between SGBS and Xq markers placed the disease locus in the interval between DXS425 and DXS1123 on Xq25-q27. Orth et al. (1994) confirmed these data by the finding of close linkage of the disease locus and the HPRT gene (maximum lod = 4.45 at theta = 0.00) in an Austrian and an Italian family.

Molecular Genetics

GPC3 Gene

Pilia et al. (1996) identified microdeletions in the GPC3 gene that cosegregated with SGBS in 3 affected families.

In affected members of a family described by Xuan et al. (1994), Xuan et al. (1999) identified a 13-bp deletion in the GPC3 gene (300037.0001). Xuan et al. (1999) confirmed their previous suggestion that a female in the family who had multiple thoracic hemivertebrae, Sprengel deformity of her right shoulder, and Wilms tumor did not carry the SGBS exon 2 deletion of the GPC3 gene. Xuan et al. (1999) suggested that the presence of skeletal abnormalities and Wilms tumor in this patient may be due to a trans effect from the maternal carrier in this SGBS kindred.

Li et al. (2001) performed GPC3 deletion screening on 80 male patients with somatic overgrowth in the following categories: 19 with Simpson-Golabi-Behmel syndrome, 26 with possible SGBS, and 35 with Beckwith-Wiedemann syndrome. Using exon-specific PCR and Southern blot analysis, 7 GPC3 deletions were identified, 6 from the SGBS category and 1 from the possible SGBS category. None of the patients with Beckwith-Wiedemann syndrome had GPC3 deletions. GPC3 deletions were identified in 2 patients from families published previously as having other overgrowth syndromes: one with a diagnosis of Sotos syndrome (117550) and the other with Perlman syndrome with nephroblastomatosis. One patient developed hepatoblastoma, which had not previously been described in SGBS. Direct sequencing of all GPC3 exons of the 13 SGBS patients without deletions failed to identify any further mutations, suggesting that alternative silencing mechanisms and/or other genes may be involved in the pathogenesis of SGBS.

Rodriguez-Criado et al. (2005) described 2 molecularly confirmed families with SGBS. All patients had typical manifestations of SGBS, including some female relatives who had minor manifestations. Some patients had novel findings such as a deep V-shaped sella turcica and 6 lumbar vertebrae. Molecular studies in affected patients showed a deletion of exon 6 of the GPC3 gene in family 1 (300037.0008) and an intronic mutation in the GPC3 gene in family 2 (300037.0009).

Romanelli et al. (2007) reported 2 brothers with SGBS caused by a truncating mutation in the GPC3 gene (300037.0010). The mutation was not present in the mother, indicating germinal mosaicism.

Sakazume et al. (2007) identified mutations in the GPC3 gene in 7 Japanese boys with SGBS. One of the boys had an affected younger brother. All the mutations were predicted to resulted in complete loss of function. Only 1 patient had a large deletion, and there were 5 nonsense and 1 frameshift mutation. There were no apparent genotype/phenotype correlations.

GPC4 Gene

Veugelers et al. (1998) found that 1 of the SGBS patients reported by Pilia et al. (1996) had a deletion of the entire GPC4 gene (300168) as well as deletion of the last 2 exons of GPC3.

In 2 males with SGBS who were part of the original family reported by Golabi and Rosen (1984), Waterson et al. (2010) found no mutations in exons or intron/exon boundaries of the GPC3 gene. However, multiple ligation-dependent probe amplification (MLPA) analysis identified a duplication of exons 1 through 9 of the GPC4 gene. Dosage studies in 1 of the patients confirmed the duplication, whereas dosage of the GPC3 gene was normal. The 2 genes are closely linked and encode similar proteoglycans. Waterson et al. (2010) suggested that the duplication may affect, and possibly decrease, expression of the GPC3 gene, thus leading to the phenotype. The phenotype of the 2 boys was consistent with SGBS, with features of an overgrowth syndrome, genitourinary anomalies, vertebral anomalies, clefting, and coarse facial features. Waterson et al. (2010) concluded that GPC4 testing should be considered in patients who have no identifiable GPC3 mutations.

History

Gurrieri et al. (2011) reported the discovery of what is believed to be the first case of SGBS on record, an infant boy born around 1940. The infant was ascertained through a male Italian proband, born in 2001, who presented with classic features of the disorder and was subsequently found to carry a truncating mutation in the GPC3 gene. Family history showed that the proband's mother, who was of above average height and developed a low-grade ovarian tumor at age 22 years, also carried the mutation in the heterozygous state. The proband's maternal grandmother also carried the mutation. Familial recollections revealed that the proband's maternal great-grandmother had 2 male macrosomic children who died in the neonatal period. One of these infants was placed in a jar in formaldehyde in the Ospedale Carlo Forlanini anatomical museum in Rome. This infant was located, noted to be macrosomic, and a skin biopsy confirmed that this boy was a carrier of the same truncating mutation found in other family members.