Perlman Syndrome

A number sign (#) is used with this entry because of evidence that Perlman syndrome is caused by homozygous or compound heterozygous mutation in the DIS3L2 gene (614184) on chromosome 2q37.

Description

Perlman syndrome is an autosomal recessive congenital overgrowth syndrome with similarities to Beckwith-Wiedemann syndrome (BWS; 130650). Affected children are large at birth, are hypotonic, and show organomegaly, characteristic facial dysmorphisms (inverted V-shaped upper lip, prominent forehead, deep-set eyes, broad and flat nasal bridge, and low-set ears), renal anomalies (nephromegaly and hydronephrosis), frequent neurodevelopmental delay, and high neonatal mortality. Perlman syndrome is associated with a high risk of Wilms tumor, with a 64% incidence in infants surviving beyond the neonatal period. The tumor is diagnosed at an earlier age in these individuals compared with sporadic cases (less than 2 years and 3-4 years of age, respectively), and there is a high frequency of bilateral tumors (55%). Histologic examination of the kidneys in children with Perlman syndrome shows frequent nephroblastomatosis, which is a precursor lesion for Wilms tumor (summary by Astuti et al., 2012).

Clinical Features

Liban and Kozenitzky (1970) and Perlman et al. (1973) described 5 offspring, of Jewish-Yemenite second-cousin parents, with a disorder manifested by large birth size, bilateral renal hamartomas with or without nephroblastomatosis, hypertrophy of the islets of Langerhans, and unusual facies. The longest survival was 27 days. There are some obvious similarities to the Beckwith-Wiedemann syndrome (130650) but the facies is thought to be characteristic with depressed nasal bridge and anteverted upper lip. Perlman et al. (1975) reported a sixth offspring from the Jewish-Yemenite family with fetal gigantism, renal hamartomas, and nephroblastomatosis, in whom Wilms tumor (194070) occurred. Perlman (1986) published very instructive photographs of the 2 sibs that he and his colleagues reported in 1973 and 1975. The remarkably similar and distinctive facies consisted of round fullness, hypotonic appearance with open mouth, a long upper lip with inverted V-shape, upsweep of anterior scalp hair, and mild micrognathia.

Neri et al. (1984) reported an affected brother and sister with unaffected, unrelated parents. The brother died suddenly at 8 months of age after a seizure during an apneic episode. His sister, who underwent surgery for Wilms tumor (194070) and removal of a recurrence at 4.5 and 5.5 years of age, respectively, with subsequent removal of a pulmonary metastasis and hamartoma at 6.5 years of age, was alive at 12 years of age. Hyperinsulinism is probably an important feature and may be a preventable cause of death. The cases of Greenberg et al. (1984, 1985, 1986) were in 2 sibs with polyhydramnios, fetal ascites, abdominal muscular hypoplasia, visceromegaly, and subsequent development of bilateral Wilms tumor in one of them. This disorder should be considered in the differential diagnosis of fetal ascites without hydrops.

Dao et al. (1987) studied chromosome 11p markers in a patient with this syndrome and found the same loss of 11p DNA sequences that occurs in Wilms tumor. Genetic differences between 2 tumors indicated that they developed independently, the results of different genetic events.

Greenberg et al. (1988) reported an infant with manifestations of Perlman syndrome, including polyhydramnios, macrosomia, bilateral nephromegaly with nephroblastomatosis, visceromegaly, and cryptorchidism. The patient also had diaphragmatic hernia and interrupted aortic arch, suggesting that these may be findings of Perlman syndrome.

Hamel et al. (1989) described additional features of volvulus and distal ileal atresia as well as agenesis of the corpus callosum. From a study of 11p markers, they found no evidence of rearrangements. Because of the overlapping of clinical features with the Beckwith-Wiedemann syndrome, the findings of a cytogenetic abnormality of chromosome 11 is of interest.

Chernos et al. (1990) described a newborn with macroglossia and bilateral hydronephrosis which had been diagnosed in utero. The infant had prominent forehead, broad flat facies, hypertelorism, bilateral epicanthic folds, deep-set eyes, a short upturned nose with wide nostrils, and prominent upper lip. Cytogenetic studies demonstrated an extra band on the tip of the short arm of one chromosome 11 which was G-dark, Q-bright, and C-negative.

Henneveld et al. (1999) reported 4 patients from 3 Dutch families with Perlman syndrome. All had typical manifestations, including macrosomia, nephromegaly with renal dysplasia, hypotonia, and characteristic facies. Additional features included dextroposition of the heart (1 patient), hepatic fibrosis with porto-portal bridging (1 patient), volvulus and intestinal atresia (1 patient), choroid plexus hemangiomas (2 patients), agenesis of the corpus callosum (1 patient), and cleft palate (1 patient). All 4 died within the first year of life. Two patients were brother and sister, supporting the hypothesis that this condition is inherited in an autosomal recessive manner.

Schilke et al. (2000) described a neonate presenting with polyhydramnios; macrosomia; macrocephaly; visceromegaly including bilateral nephromegaly, hepatomegaly, and cardiomegaly; thymus hyperplasia; cryptorchidism; generalized muscle hypotonia; and a distinctive facial appearance. The clinical course was marked by severe neurodevelopmental deficits combined with progressive respiratory decompensation, leading to death at the age of 6 months. MRI disclosed a generalized cerebral atrophy with a marked deficit of the white matter. Renal ultrasound and MRI showed markedly enlarged kidneys with multiple small cystic lesions, a pattern indistinguishable from polycystic kidney disease. The postmortem kidney biopsy showed dysplastic changes, microcysts, and a focal nephrogenic rest, characteristic features of the Perlman syndrome. The parents were nonconsanguineous, healthy Albanians.

Piccione et al. (2005) reported the 9-year follow-up of a girl with Perlman syndrome. She was born of nonconsanguineous parents by cesarean section due to polyhydramnios and at birth was noted to have macrosomia, macrocephaly, prominent forehead, full round face, deeply set eyes, hypertelorism, epicanthic folds, broad flat nasal bridge, anteverted upper lip, highly arched palate, dysplastic ears, and axial hypotonia, but no organomegaly. At 6 months of age she was noted to have mild hepatosplenomegaly and bilateral nephromegaly; Wilms tumor was diagnosed at 20 months of age. When seen at age 9, she had macrocephaly, severe right convex dorsal and left convex lumbar scoliosis, lumbar hyperlordosis and asymmetry of the iliac crests, and prominent xiphisternum. Psychomotor development was normal.

Alessandri et al. (2008) reported an infant with Perlman syndrome who died at 2 days of age. Prenatal ultrasound showed enlarged kidneys and marked ascites. After birth, she was found to have macrosomia, abdominal distention, nephromegaly, hypoplastic thorax, characteristic face with depressed nasal bridge, deep-set eyes, low-set dysplastic ears and micrognathia. Renal biopsy showed bilateral nephroblastomatosis. A previous pregnancy resulted in an infant who rapidly expired after birth and probably had the same syndrome. Alessandri et al. (2008) reviewed 28 patients with typical Perlman syndrome and concluded that there is a high neonatal mortality rate. Most affected infants developed respiratory distress with refractory hypoxemia and/or renal failure and died within the first hours or days of life.

Mapping

In a consanguineous Pakistani kindred with Perlman syndrome, in which mutation in the IGF2 (147470) and IGF2R (147280) candidate genes had been excluded, Astuti et al. (2012) performed autozygosity mapping by genomewide SNP genotyping and identified 8 regions of extended homozygosity, including a 43-cM (28-Mb) region on chromosome 2q. Analysis of 3 affected individuals from 2 potentially consanguineous Dutch kindreds with Perlman syndrome, previously reported by Henneveld et al. (1999), confirmed the autozygous region at 2q37 and narrowed it to a 4.8-cM (2.1-Mb) interval between rs1992188 and rs1104953.

Molecular Genetics

In a consanguineous Pakistani kindred and 2 Dutch kindreds with Perlman syndrome mapping to chromosome 2q37, Astuti et al. (2012) analyzed 36 candidate genes and identified a failure to amplify exons 6 and 9, respectively, of the DIS3L2 gene (614184). Further investigation revealed that affected individuals in the Pakistani family were homozygous for an 82.8-kb deletion in DIS3L2 (614184.0001), whereas patients from the 2 Dutch families previously studied by Henneveld et al. (1999), as well as an unrelated Dutch patient, were homozygous for an approximately 22-kb deletion (614184.0002). Analysis of DIS3L2 in cell lines from 2 additional unrelated children with Perlman syndrome, 1 of whom was the sister previously studied by Neri et al. (1984), revealed compound heterozygous mutations (614184.0002-614184.0004).