Perlman syndrome

Overview

Perlman syndrome is a rare, congenital overgrowth disorder characterized by macrosomia (excessive birth weight), distinctive facial features, nephroblastomatosis (abnormal kidney development), and a significantly increased risk of developing Wilms tumor, a pediatric kidney cancer. It is classified as an autosomal recessive genetic condition and often presents at birth or in the prenatal period. The syndrome is part of a group of pediatric overgrowth syndromes, which includes Beckwith–Wiedemann syndrome and Sotos syndrome. Unfortunately, Perlman syndrome is frequently associated with poor outcomes due to severe developmental abnormalities and a high risk of neonatal mortality.

Causes

Perlman syndrome is caused by mutations in the DIS3L2 gene, which is located on chromosome 2q37. This gene plays a role in RNA metabolism and cell proliferation. The loss of function of DIS3L2 disrupts cellular growth regulation, contributing to the characteristic overgrowth and tumor predisposition seen in the syndrome.

The condition is inherited in an autosomal recessive pattern, meaning that an affected child must inherit two copies of the mutated gene—one from each parent. Carriers, who have only one mutated copy, do not show symptoms but can pass the mutation on to their offspring.

Symptoms

Perlman syndrome has a range of clinical features that vary in severity. Common signs and symptoms include:

Growth and Developmental Features:

• Macrosomia: Excessive growth during pregnancy and large birth size

• Neonatal hypotonia: Poor muscle tone at birth

• Developmental delays: In survivors, intellectual and motor delays are common

Craniofacial Features:

• Coarse facial features

• Deep-set eyes

• Prominent forehead (frontal bossing)

• Broad nasal bridge and upturned nose

• Macroglossia (enlarged tongue)

Genitourinary and Abdominal Findings:

• Nephromegaly: Enlarged kidneys often present at birth

• Nephroblastomatosis: Abnormal kidney tissue with potential to develop into Wilms tumor

• Cryptorchidism: Undescended testes in males

Other Possible Features:

• Umbilical hernia

• Polyhydramnios (excess amniotic fluid during pregnancy)

• Visceromegaly (enlargement of internal organs)

• Congenital heart defects (less common)

Many infants with Perlman syndrome experience complications soon after birth, including respiratory distress and renal failure.

Diagnosis

Diagnosis of Perlman syndrome is often based on clinical features and family history, with genetic testing used to confirm the diagnosis.

Diagnostic Steps:

• Prenatal ultrasound: May reveal signs of macrosomia, polyhydramnios, and enlarged kidneys

• Postnatal physical examination: Identification of characteristic facial features and overgrowth

• Imaging studies: Abdominal ultrasound or MRI to evaluate kidney size and detect nephroblastomatosis

• Histological examination: Kidney biopsy in some cases shows nephroblastomatosis

• Genetic testing: Confirmation via detection of biallelic pathogenic variants in the DIS3L2 gene

Differential diagnosis includes other overgrowth syndromes like Beckwith–Wiedemann syndrome and Simpson–Golabi–Behmel syndrome, which must be excluded through clinical and molecular evaluation.

Treatment

There is no cure for Perlman syndrome, and treatment is primarily supportive and symptom-based. A multidisciplinary team approach is required for management, especially in the neonatal period and early childhood.

Supportive Care:

• Neonatal intensive care: Required for respiratory support, feeding, and monitoring organ function

• Management of hypotonia: Physical therapy to support motor development

• Developmental support: Early intervention programs, speech and occupational therapy

Surveillance and Medical Management:

• Regular abdominal ultrasounds: To monitor for Wilms tumor development, especially in the first years of life

• Nephrology care: For renal function monitoring and management of nephromegaly or kidney failure

• Surgical interventions: May be needed for cryptorchidism, umbilical hernias, or tumor resection if Wilms tumor develops

In cases where Wilms tumor develops, treatment may involve chemotherapy and surgical tumor removal, following pediatric oncology protocols.

Prognosis

The prognosis for individuals with Perlman syndrome is generally poor due to the severity of neonatal complications and high mortality rate in infancy. Many affected infants do not survive beyond the first few weeks or months of life due to renal failure, respiratory issues, or other congenital anomalies.

For those who survive the neonatal period, the risk of Wilms tumor remains significant, requiring close oncologic surveillance. Survivors may face lifelong challenges related to developmental delay and organ dysfunction. Early diagnosis, intensive medical care, and vigilant tumor monitoring are essential for improving outcomes.

Genetic counseling is highly recommended for families affected by Perlman syndrome to understand recurrence risks and to explore options such as prenatal testing in future pregnancies.