Hemihyperplasia, Isolated

Description

Isolated hemihyperplasia is an abnormality of cell proliferation leading to asymmetric overgrowth of one or more regions of the body. The term 'hemihyperplasia' has replaced the term 'hemihypertrophy' to describe accurately the increase in cell number found in these patients. The incidence of isolated hemihyperplasia is estimated to be 1 in 86,000. Idiopathic hemihypertrophy is associated with increased risk of embryonal cancers in childhood, particularly Wilms tumor (194070) (Shuman et al., 2006).

Hoyme et al. (1998) provided an anatomic classification of hemihyperplasia: complex hemihyperplasia is involvement of half of the body, including at least 1 arm and 1 leg; affected parts may be contralateral or ipsilateral. Simple hemihyperplasia is involvement of a single limb. See also facial hemihyperplasia (133900).

Although isolated hemihyperplasia is a distinct clinical entity, it can also occur as a feature of overgrowth syndromes, including Beckwith-Wiedemann syndrome (BWS; 130650), neurofibromatosis (NF1; 162200), Proteus syndrome (176920), and Klippel-Trenaunay-Weber syndrome (149000) (Shuman et al., 2006).

Clinical Features

There are several early reports of familial hemihypertrophy (Reed, 1925; Scott, 1935; Arnold, 1936; Rudolph and Norvold, 1944; Morris and MacGillivray, 1955). However, some of these patients had additional findings, suggesting that not all of the families had isolated hemihyperplasia (Heilstedt and Bacino, 2004).

Fraumeni et al. (1967) described affected brother and sister and recorded that their maternal uncle was said to have had one leg longer than the other since childhood. They reviewed 6 other examples of familial occurrence with instances of successive generations affected.

Meadows et al. (1974) reported the development of Wilms tumor in 3 children of a woman with congenital hemihypertrophy. Frota-Pessoa (1979) reported a nonconsanguineous Polish-Brazilian family with possible involvement in grandfather, mother, and mother's sister and grandson.

Viljoen et al. (1984) reported 11 unrelated individuals with congenital idiopathic hemihypertrophy defined as unilateral overgrowth of the body noted at birth. Overgrowth was left-sided in 8 and right-sided in 3. All except 1 patient had low or low-normal intelligence. Three patients had seizures, and 1 each had undescended testes, inguinal hernia, communicating hydrocephalus, bicuspid aortic valve, and Cushing syndrome. There was no difference in bone age between the hypertrophied and normal parts, and relative body proportions remained the same during growth. No genetic or other etiologic factors were recognized in this series.

Stoll et al. (1993) reported 12 patients with hemihypertrophy. One patient had some features of McCune-Albright syndrome (174800) and 2 had Silver-Russell syndrome (180860). The remaining 9 patients had idiopathic isolated hemihypertrophy. There was 1 familial occurrence in a mother and daughter. Body symmetry was unchanged during growth, and orthopedic problems, particularly scoliosis, complicated some cases. The right and left sides were essentially equally affected; limb length differences ranged from 1 to 6 cm. One patient developed a nephroblastoma.

In a prospective multicenter study of 168 children with isolated hemihyperplasia, Hoyme et al. (1998) found that 9 children developed tumors, yielding an overall incidence of 5.9%. Tumors were of embryonal origin similar to those noted in other overgrowth disorders: 4 unilateral Wilms tumors, 2 bilateral Wilms tumors, 2 adrenal cell carcinomas, 1 hepatoblastoma, and 1 leiomyosarcoma of the small bowel.

In the course of reviewing their experience with 18 patients with a referring diagnosis of Proteus syndrome, Biesecker et al. (1998) found that Proteus syndrome is frequently confused with hemihyperplasia. They defined a distinct subtype of hemihyperplasia with static or mildly progressive hemihyperplasia and multiple lipomata. They referred to this as the hemihyperplasia-multiple lipomatosis syndrome and suggested that this provisional designation may prove to be a useful description for a group of patients that show moderate abnormalities of asymmetry and overgrowth with subcutaneous lipomata. The manifestations in all but 1 of these patients were relatively stable from infancy through preadolescence. One subject showed evidence of severe progressive lipomatosis in his first 2 years of life.

Van den Akker et al. (2002) reported a 19-year-old woman with congenital hemihypertrophy of the right side who developed bilateral benign pheochromocytomas. The first pheochromocytoma was on the right side and developed at age 12 years; the second was on the left side and developed at age 17 years. The right adrenal cortex showed nodular hyperplasia. She also had a fibroadenoma of the right breast at age 11 years. Although there was no clear additional evidence of an associated syndrome, the authors suggested that this patient's symptoms could be part of a spectrum of Beckwith-Wiedemann syndrome, even though no BWS-specific gene defects were found.

Slavotinek et al. (2003) described a family in which the propositus had overgrowth of the left side of his chest compared to the right side and his mother had overgrowth involving her left leg. The enlargement was noted in early adolescence in both family members. The propositus and his mother had increased birth weights, but did not fulfill diagnostic criteria for Beckwith-Wiedemann syndrome or have physical anomalies consistent with a syndromic form of hyperplasia. Slavotinek et al. (2003) reviewed previously reported familial cases of nonsyndromic hyperplasia and concluded that there are no clinical features differentiating familial from nonfamilial cases.

Heilstedt and Bacino (2004) reported a Tunisian family in which 3 maternal cousins and their maternal grandfather had isolated hemihyperplasia. The proband was a 2-year-old child who had hyperplasia of the right upper and lower extremities. The length and diameter of the right leg and calf were 3 cm longer and 3 cm larger, respectively, compared to the left. There were no other anomalies, but the child developed Wilms tumor at age 2 years. Two maternal cousins of the proband and the maternal grandfather also had isolated hemihyperplasia. No cytogenetic abnormalities were detected in the 11p15 region in 2 patients examined. Heilstedt and Bacino (2004) suggested autosomal dominant inheritance with incomplete penetrance and postulated an imprinting defect of the maternally derived chromosome in the grandfather.

Hemi-3 Syndrome

Nudleman et al. (1984) reported 3 unrelated girls with what they considered to be a subtype of hemihypertrophy, designated the hemi-3 syndrome, which also showed hemihypesthesia, hemiareflexia, and scoliosis. In the enlarged part, muscles were increased in size and strength; bones were increased in thickness but not length. Hypertrophy involved one side or quadrant, on the left in all 3, sparing the face. The neurologic defect was stationary but the scoliosis, which was convex to the left, was progressive, requiring treatment. In addition, 1 patient had a lumbar myelomeningocele and all 3 had a family history of other neural tube defects (NTD; 182940). The authors proposed that the hemi-3 syndrome is a manifestation of neural tube defects, part of a spectrum of genetically and embryologically related CNS malformation with multifactorial inheritance.

Mapping

Mannens et al. (1987) studied a 3-generation family with hemihypertrophy and a case of Wilms tumor. Using 6 different RFLPs of chromosome 11p, they found that a combination of alleles cosegregated with hemihypertrophy in this family.

Molecular Genetics

West et al. (2003) described a pair of female monozygotic twins discordant for isolated hemihypertrophy, and showed mosaic paternal uniparental disomy for 11p15 in the affected twin. They proposed that isolated hemihypertrophy is, in fact, part of the spectrum of phenotypes of Beckwith-Wiedemann syndrome, which maps to 11p15.5. In addition, they proposed that postzygotic recombination resulting in uniparental disomy for 11p15 is one mechanism responsible for discordance of phenotype between monozygotic twins.

Martin et al. (2005) performed methylation studies of the LIT1 (604115) and H19 (103280) genes on chromosome 11p in 27 children with isolated hemihyperplasia. Eight children (29.6%) had a defect in methylation of 1 or both of these genes, which supported the authors' hypothesis that these epigenetic changes can result in a phenotype distinct from typical BWS.

Idiopathic hemihypertrophy is associated with increased risk of embryonal cancers in childhood. Niemitz et al. (2005) compared the constitutional epigenetic alterations associated with idiopathic hemihypertrophy with those that had been well characterized in BWS, particularly the alterations in imprinted genes on 11p15. They found that the frequency of hypermethylation of H19 in children with idiopathic hemihypertrophy and Wilms tumor, 20% (3/15), was significantly lower than the frequency in children with BWS and Wilms tumor, 79% (11/14; P = 0.0028). These results indicated that children with IH and Wilms tumor have different constitutional epigenotypes from those of children with BWS and Wilms tumor.

Shuman et al. (2006) found that 8 (16%) of 51 patients with isolated hemihypertrophy had paternal uniparental disomy of 11p15, 3 (6%) had hypomethylation at KCNQ10T1 (LIT1), and none had hypomethylation at H19. There was evidence for somatic mosaicism in all 8 cases of uniparental disomy. Four (50%) of the 8 patients with uniparental disomy had tumors, whereas only 6 (15%) of the 40 patients without molecular alterations had tumors. The findings suggested that uniparental disomy at 11p15 in patients with isolated hemihypertrophy confers a high tumor risk. Two of the 8 patients with uniparental disomy were conceived using assisted reproductive technologies; the authors postulated that these methods may impact the rate of somatic recombination during embryonic development.