Received Date: Sep 13, 2017 / Accepted Date: Dec 11, 2017 / Published Date: Dec 18, 2017
Background: Hemihypertrophy is a condition in which one side or part of the body is larger than the other. The asymmetry can range from mild to severe. It is important to establish a diagnosis because hemihypertrophy is associated with an increased risk for embryonal tumors, mainly Wilms tumor and hepatoblastoma.
Patients and Methods: This study presents ten Egyptian children with variable extent of congenital hemihypertrophy. It included 5 males and 5 females ranging in age from 2 months to 13 years. Abdomino-pelvic ultrasonography, echocardiography, brain MRI and radiological assessment of apparent and possibly hidden bone hypertrophy were performed to all cases.
Results: Cases were classified into Isolated hemihypertrophy (IH) (5 cases), part of overgrowth syndromes (3 cases) and hemihypertrophy with other malformations not fitting any of the known overgrowth syndromes (2 cases). IH cases were subclassified into simple hemihypertrophy (3 cases) and complex hemihypertrophy (2 cases). All cases were sporadic. None of our cases showed malignant transformation.
Conclusion: Hemihypertrophy may be isolated or associated with other congenital malformations. Most isolated cases are sporadic in inheritance with low recurrence risk. Screening for whole body systems is important to detect visceromegaly or other congenital anomalies. Follow up is essential to help in better diagnosis, counseling regarding the course of the disease and the recurrence risk and for early detection of malignancies. Molecular studies will help early diagnosis and distinguishing different hemihypertrophy syndromes.
Keywords: Asymmetry, Hemihyperplasia, Hemihypertrophy, Overgrowth syndrome
The asymmetric overgrowth, usually termed hemihypertrophy, is more accurately referred to as hemihyperplasia, since the pathology involves an abnormal proliferation of cells (hemihyperplasia), not an increase in size of existing cells (hemihypertrophy) . The asymmetry can be due to differences in the growth of soft tissue, bone, or both  Hemihyperplasia may be an isolated finding, or it may be part of multiple malformation syndromes, such as Russell-Silver syndrome, Proteus syndrome, Beckwith-Wiedemann Syndrome (BWS), and Sotos syndrome [3,4]. Isolated hemihyperplasia (IH, OMIM 235000) is defined as asymmetric regional body overgrowth due to an underlying abnormality of cell proliferation without any other underlying diagnosis . Rowe  proposed a classification system for hemihyperplasia, based on anatomic site of involvement. According to this classification, complex hemihyperplasia is defined as involvement of half of the body (at least one leg and one arm), simple hemihyperplasia is the involvement of a single limb and hemifacial hyperplasia is the involvement of one side of the face. The etiology of IH is unknown. A number of different chromosomal anomalies, including trisomy  mosaicism and diploidtriploid mosaicism, have been identified, and the causes of IH are likely to be heterogeneous . It has been suggested that IH could be one end of the spectrum of phenotypes of BWS , linked to the chromosomal locus 11p15 . BWS is frequently recognizable because of characteristic features as hemihypertrophy, macroglossia, omphalocele, and organomegaly. The most common molecular cause is hypomethylation of the maternal imprinting control region 2 (ICR2) in 11p15.
Somatic activating mutations in the phosphatidylinositol-3- kinase/AKT/mTOR pathway underlie different segmental overgrowth phenotypes. Historically, the clinical diagnoses in patients with PIK3CA activating mutations have included Hemihyperplasia Multiple Lipomatosis (HHML), Vascular Malformations, Scoliosis/Skeletal and Spinal (CLOVES) syndrome, macrodactyly and the related megalencephaly syndromes, Megalencephaly-Capillary Malformation Polymicrogyria (MCAP or M-CM) and Dysplastic Megalencephaly (DMEG) .
MCAP is characterized by primary megalencephaly, prenatal overgrowth, brain and body asymmetry, digital anomalies consisting of syndactyly with or without postaxial polydactyly, cutaneous vascular malformations, connective tissue dysplasia involving the skin, joints and subcutaneous tissue, and cortical brain malformations, most commonly polymicrogyria [11,12]. This disorder is also known as the macrocephaly-capillary malformation (MCM) syndrome . Mirzaa, et al.  suggested the use of the term MCAP rather than MCM to reflect the very large brain size, not simply large head size that characterizes this syndrome. Russell-Silver syndrome is a disorder present at birth that involves, low birth weight, poor growth, short stature, and body asymmetry. Characteristic features include triangular face, pointed, small chin and thin mouth .
Edmondson and Kalish  have reported elevated risk of neoplasm development in overgrowth disorders. Increased risk of embryonal tumors in cases with IH, is documented in case reports and prospective study by Hoyme et al . They followed 168 children with IH for 10 years and reported 10 tumors in 9 cases including Wilms tumors (WTs), adrenal cell carcinomas, hepatoblastoma (HBL), and small bowel leiomyosarcoma, giving a tumor incidence of 5.9%. Clericuzio, et al.  described five children (two with IH and three with BWS) for whom serial serum alpha-fetoprotein screening and abdominal ultrasound, led to early detection of HBL. Tan, et al.  have recommended measuring serum alpha-fetoprotein (AFP) every 3 months until age 4, by which time 90% of HBL will have developed. Caution in interpretation of infant AFP levels is important, as high levels of AFP is present at birth which fall rapidly to the normal adult level by 10-12 months of age [19,20].
Patients and Methods
The present study comprised ten Egyptian children with congenital hemihyperplasia. They consisted of 5 males and 5 females ranging in age from 2 months to 13 years. All patients were selected from among patients attending the outpatient Genetics clinic, Faculty of medicine, Fayoum University, Egypt, over a period of twenty-three months starting October 2013 through August 2015. Informed consent had been signed by all studied patients and their guardians according to the guidelines of the Medical Research Ethics Committee at Fayoum University. Enrolled cases were subjected to complete prenatal, personal and family histories with pedigree construction and full clinical examination. Abdominopelvic ultrasonography, echocardiography, brain MRI and radiological assessment of apparent and possibly hidden bone hyperplasia were performed to all cases.
Ten cases were presented with variable extent of hemihyperplasia Table 1. Positive consanguinity was present in 5 cases (50%) (Figure 1). None of our cases had similarly affected family members. Prenatal histories were relevant in two cases (20%). One case had a history of maternal electric shock exposure at 5th gestational months and the other case had prenatal history of progesterone hormonal preparations intake from the second gestational month to the end of pregnancy. Eight cases (80%) had associated cutaneous lesions at different sites of their bodies. Two cases (20%) had dysmorphic features; (case no.2: depressed nasal bridge, hypertelorism, prominent forehead and bilateral simian creases; and case no 10: Triangular face, micrognathia and clinodactyly of little fingers) (Figure 2). Two cases (20%) had associated limb anomalies; case no 2 had right post axial polydactyly of toes; and case no 5 had partial soft tissue syndactyly between second and third toes of right foot. Three cases (no 1, 2 and 3) (30%) had delayed milestones of development out of which two cases had history of seizures. One case (no 3) (10%) had atrial septal defect with mild pericardial effusion (Figure 3). One case (no 10) (10%) had associated malrotated ectopic left kidney. One case (no 5) (10%) had undescended left testis. Case no 2 met the criteria of MCM syndrome and another case with hemifacial hyperplasia was diagnosed as SWS. Case no 10 (Figure 4) was diagnosed as Silver Russell syndrome. Two cases had complex hemihyperplasia in association with other malformation; which did not meet any of the known overgrowth syndromes. IH was diagnosed in five cases (50%) whom according to the proposed calcification of Rowe , were subclassified into simple hemihyperplasia (three cases 30%) and complex hemihyperplasia (two cases 20%). Follow up visits of our patients showed no sonographic findings of malignancy. In an attempt of cosmetic surgical correction, one case with isolated macrodactyly of left middle finger had an operation to reduce its size but unfortunately it increased in size later.
|Patient1||Patient 2||Patient 3||Patient 4||Patient 5||Patient 6||Patient 7||Patient 8||Patient 9||Patient 10|
|Age||2 y||2 m||6 m||9 m||6 y||13 y||1 y||7 m||4 m||3 m|
|Prenatal insults||no||no||Yes Electric shock and fainting||no||no||no||No||Yes Progesterone injections||no||no|
|Hypertrophy site||Rt cheek (face)||Face, Lower limbs||Rt. Upper& Lower limbs||Lt.arm||All Toes||Lt. Middle finger||Lt. 2nd, 3rd, 4th toes||Rt. hand Lower limbs||Rt. Upper &lower limbs||Skull, Rt.leg|
|Skin pigmentation||Facial hemangioma (Rt cheek, skin over Rt. mandible, Rt shoulder, lt. forehead and cheek)||Extensive hema.||no||Hema. of Lt.arm& shoulder||Café aulait patches on lt.hypochondrial&iliac regions||Café aulait patches on Rthypochondrial and l\Lt scapular regions||Hypopig-mented areaon anterior aspect of Lt. thigh||Small hema. on forehead||no||Hema. on lower back of head|
|Other malformation||Bil. glaucoma||Polydactyly of toes. Hemimegalencephaly||Dysmorphic Bil. Simian creases||no||Syndactyly of Rt. Toes. Undescended testis||no||no||no||no||Triangular face, pointed chin|
|Brain CT/ MRI||Lt cerebral hemiatrophy||Lt.cerebralhemimegalencephaly&schizencephaly||Dilated ventricles||Normal||Normal||Normal||_||N||_||N|
|Other investigations||EEG: Lt hypoactive record||Echo, Abd U/S : N||Echo: ASD Abd. U/S: N||Echo, Abd U/S: N||Abd. U/S: undesended testis||Echo, Abd U/S: N||Abd U/S: N||Karyotype, Echo, Abd U/S: N||Abd U/S: N||Abd U/S: malrotated ectopic Lt kidney|
|Diagnosis||Sturge Weber syndrome (Hemifacial hypertrophy)||Megalencephaly Capillary Malformation Syndrome||?Syndromic (+ASD, Dysmorphism)||Simple Hemihyertrophy||?Syndromic (+ undescended testis, syndactyly)||Simple Hemihyertrophy||Simple Hemihyertrophy||Complex Hemihypertrophy||Complex Hemihypertrophy||Russell Silver syndrome|
Table 1: History, clinical description and imaging data of cases with hemihypertrophy in this study.
Figure 4: Patient no 1: 2 years old child diagnosed as Sturge Weber syndrome. There is associated right hemifacial hypertrophy. Congenital hemangioma affecting skin over right cheek, mandible and extends to right shoulder. The child had delayed motor and mental milestones and bilateral congenital glaucoma. Brain CT showed reduce volume of left cerebral hemisphere with prominent leptomeningeal enhancement and enlarged ipsilateral choroid plexus. EEG showed left side hypoactivity.
Hemihyperplasia, is a condition in which there may be asymmetrical overgrowth of the face, cranium, trunk, and/or limbs on one side of the body [21,22]. There may be asymmetrical visceromegaly on the ipsilateral or contralateral side . The incidence of IH is ∼1/86 000 live births, [7,23] with a male: female ratio of 1:2  . In the current study, all cases were sporadic and had negative family history with male to female ratio of 1:1. Isolated hemihyperplasia is usually sporadic with low recurrence risk. Barsky  and others found no report of familial occurrence. On the other hand, there have been many reports of familial hemihyperplasia in the literature with two or more affected relatives [24-32]. However, some of these patients had additional features, suggesting that not all of the families had IH . In this study, we had five cases (50%) with IH; all were sporadic with no similar affected relatives. Three cases with IH had history of positive consanguinity.
Lacombe and Battin  described 2 children diagnosed at birth as isolated megalodactyly. Their follow-up examination showed development of hemihypertrophy and other findings suggesting Proteus syndrome . However, our case (case no 6) had isolated megalodactyly of right middle finger. Megalodactyly was present since birth and had increased in length and thickness over time without involvement of other parts or organs. The child had three oval café au lait patches on right hypochondrium and two on left scapular region. Greene, et al.  stated that facial hypertrophy is a major component of SWS; and patients should be counseled for the risk of overgrowth and for the types of possible surgical correction. However, hemifacial hyperplasia maybe also present as isolated malformation. Deshingkar, et al.  reported a mentally healthy 12-year old boy with isolated hemifacial hypertrophy. The patient’s face was asymmetrical with an enlargement of the right side, including the maxillary, malar, and mandibular region. Our case of SWS (case no. 1) is a 2-year old male child with history of global developmental delay and seizures. He has hemifacial hypertrophy of the right side, including the malar, maxillary and mandibular regions. Similarly, Babaji, et al.  presented a case of SWS with osseous hypertrophy of maxilla.
Kumar, et al.  presented a 15-year-old boy with Silver-Russell syndrome. He was well-appearing, thin, and short with normal head circumference. Asymmetry of his hands, phalanges, and lower extremities were noted, with hemihypertrophy of the left lower extremity. Similarly, our case (case no 10) is a 3-month old girl with typical features suggestive of Silver-Russell syndrome [35,36] . She has hypertrophy of right side of the skull and her right lower limb is longer and thicker than her left lower limb. Follow up visits showed the discrepancy of limbs size and length and the skull asymmetry. She had poor weight gain and short stature but she had within normal milestones of development. On Review of literature, case no. 2 had features suggestive of MCAP (OMIM # 602501) overlapping with megalencephaly, polymicrogyria-polydactyly hydrocephalus syndrome (MPPH; OMIM, 603387). These features are congenital macrocephaly, cranium and face asymmetry, bilateral lower limbs hyperplasia, right post axial polydactyly of toes, massive body hemangioma with brain MRI showing hemimegalencephaly of left cerebral hemisphere with closed lip schizencephaly, periventricular band like heterotopia and areas of lissencephaly. Mirzaa, et al.  reviewed the phenotypic features of 42 patients with a megalencephalic syndrome in a trial to clarify and simplify the classification and diagnosis of these disorders. Statistical analysis of particular features yielded 2 major groups: 21 patients with a vascular malformation consistent with MCAP and 19 with no vascular malformation consistent with MPPH; 2 patients were in an overlap group. Vascular malformations were associated with syndactyly and somatic overgrowth at birth, and lack of vascular malformations was associated with polydactyly. The different features were assigned to 5 major classes of developmental malformations. Both MCAP and MPPH had (1) megalencephaly and different somatic overgrowth (specially in MCAP); (2) distal limb malformations, polydactyly being more associated with MPPH and syndactyly with MCAP and (3) similar cortical brain malformations (mostly polymicrogyria). In addition, MCAP included (4) Vascular abnormalities and (5) occasional connective tissue dysplasia, such as thick skin or hyperelasticity. MPPH lacks connective tissue dysplasia, vascular malformations, and heterotopia. Based on these findings, Mirzaa, et al.  proposed diagnostic criteria for MPPH and MCAP syndromes, and postulated that the 2 malformations represent different, although overlapping, syndromes that possibly caused by different genes involved in the same biologic pathway. Our case had right postaxial polydactyly of toes which is more common in MPPH, in association with vascular malformations and left cerebral hemisphere megalencephaly with heterotopia which are mainly features of MCAP.
Hemihyperplasia/hemihypertrophy has an extremely variable presentation. It may be isolated or part of a syndrome. Most isolated cases are sporadic in inheritance with low recurrence risk. Many syndromes with hemihyperplasia are well recognized. Screening for whole body systems is important to detect visceromegaly or other congenital anomalies or malignancies. Follow up is essential to help in better diagnosis, counseling regarding the course of the disease and the recurrence risk and for early detection of malignancies. Molecular studies will help early diagnosis and distinguishing different hemihypertrophy syndromes to predict other associated malformations for early and better management.
Authors would like to thank all patients and their family.
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
- Cohen MM Jr (1989): A comprehensive and critical assessment of overgrowth and overgrowth syndromes. Adv Hum Genet 18: 181-303, 373-376.
- Clericuzio CL and Martin RA (2009): Diagnostic criteria and tumor screening for individuals with isolated hemihyperplasia. Genet Med 11:220-222.
- Ballock RT, Wiesner GL, Myers MT, Thompson GH (1997): Hemihypertrophy. Concepts and controversies. J Bone Joint Surg Am 79:1731-1738.
- Clericuzio CL (1999) : Recognition and management of childhood cancer syndromes: A systems approach. Am J Med Genet 89:81-90.
- Hoyme HE, Seaver LH, Jones KL, Procopio F, Crooks W, et al. (1998): Isolated hemihyperplasia (hemihypertrophy): report of a prospective multicenter study of the incidence of neoplasia and review. Am J Med Genet 79:274-278.
- Rowe NH (1962): Hemifacial hypertrophy: Review of the literature and addition of four cases. Oral Surg 15:572-576.
- Ringrose RE, Jabbour JT, Keele DK (1965): Hemihypertrophy. Pediatrics 36:434-448.
- Pappas JG (2015): The clinical course of an overgrowth syndrome, from diagnosis in infancy through adulthood: the case of Beckwith-Wiedemann syndrome. Curr Probl Pediatr Adolesc Health Care 45: 12-17.
- Cohen MM Jr. (2001): Asymmetry: molecular, biologic, embryopathic, and clinical perspectives. Am J Med Genet 101:292-314.
- West PMH, Love DR, Stapleton PM, Winship IM (2003): Paternal uniparental disomy in monozygotic twins discordant for hemihypertrophy. J Med Genet 40:223-226.
- Keppler-Noreuil KM, Rios JJ, Parker VE, Semple RK, Lindhurst MJ, et al. (2015): PIK3CA-related overgrowth spectrum (PROS): diagnostic and testing eligibility criteria, differential diagnosis, and evaluation. Am J Med Genet A 167A:287-295.
- Mirzaa GM, Conway RL, Gripp KW, Lerman-Sagie T, Siegel DH, et al. (2012) : Megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes: two closely related disorders of brain overgrowth and abnormal brain and body morphogenesis. Am. J. Med. Genet. 158A: 269-291.
- Conway RL, Pressman BD, Dobyns WB, Danielpour M, Lee J, et al. (2007). Neuroimaging findings in macrocephaly-capillary malformation: a longitudinal study of 17 patients. Am. J. Med. Genet 143A: 2981-3008.
- Kumar S, Jain AP, Agrawal S, Chandran S (2008) : Silver-Russell Syndrome: A Case Report. Cases Journal 1:304.
- Edmondson Andrew C, Kalish Jennifer M (2015): Overgrowth Syndromes. J Pediatr. Genet 4: 136–143.
- Clericuzio CL, Chen E, McNeil DE, O'Connor T, Zackai EH (2003) : Serum alpha-fetoprotein screening for hepatoblastoma in children with Beckwith-Wiedemann syndrome or isolated hemihyperplasia. J Pediatr 143:270-272.
- Tan TY, Amor DJ (2006): Tumour surveillance in Beckwith-Wiedemann syndrome and hemihyperplasia: a critical review of the evidence and suggested guidelines for local practice. J Paediatr Child Health 42: 486-490.
- Tsuchida Y, Endo Y, Saito S, Kaneko M, Shiraki K, et al. (1978): Evaluation of alpha-fetoprotein in early infancy. J Pediatr Surg 13:155-162.
- Ohama K, Nagase H, Ogino K, Tsuchida K, Tanaka M, et al. (1997): Alpha-fetoprotein (AFP) levels in normal children. Eur J Pediatr Surg 7:267-269.
- Rowe NH (1962): Hemifacial hypertrophy: Review of the literature and addition of four cases. Oral Surg 15:572-576.
- Henry I, Puech A, Riesewijk A, Ahnine L, Mannens M, et al. (1993): Somatic mosaicism for partial paternal isodisomy in Wiedemann-Beckwith syndrome: a post-fertilization event. Eur J Hum Genet 1:19-29.
- Tomooka Y (1988): Congenital hemihypertrophy with adrenal adenoma and medullary sponge kidney. Br J Radiol 61:851-853.
- Barsky AJ (1967): Macrodactyly. J. Bone Joint Surg Am 49: 1255-1266.
- Heilstedt Heidi A, Bacino Carlos A (2004): A case of familial isolated hemihyperplasia. Med Genet 5: 1.
- Lacombe D, Battin J (1996): Isolated macrodactyly and Proteus syndrome. (Letter) Clin. Dysmorph 5: 255-257.
- Rudolph CE, Norvold RW (1994): Congenital Partial Hemihypertrophy Involving Marked Maloclusion. J Dent Res 23:133-139.
- Morris JV, Mac Gillivray RC (1955): Mental Defect and Hemihypertrophy. Am J Ment Defic 59:645-650.
- Fraumeni JF Jr, Geiser CF, Manning MD (1967): Wilms' tumor and congenital hemihypertrophy: report of five new cases and review of literature. Pediatrics 40:886-899.
- Reed EA (1925): Congenital total hemihypertrophy. Arch. Neurol. Psychiat 14: 824-831.
- Scott AJ (1935): Hemihypertrophy: report of four cases. J. Pediat 6: 650-655.
- Greene AK, Taber SF, Ball KL, Padwa BL, Mulliken JB (2009): Sturge-Weber syndrome: soft-tissue and skeletal overgrowth. J Craniofac Surg 20 Suppl 1: 617-621
- Deshingkar SA, Barpande SR, Bhavthankar JD (2011): Congenital hemifacial hyperplasia. Contemp Clin Dent. 2: 261-264.
- Babaji P, Bansal A, Choudhury GK, Nayak R, Kodangala Prabhakar A, et al. (2013): Sturge-weber syndrome with osteohypertrophy of maxilla. Case Rep Pediatr 964596.
- Kumar S, Jain AP, Agrawal S, Chandran S (2008): Silver-Russell Syndrome: A Case Report. Cases Journal 1:304.
- Slatter RE, Elliott M, Welham K, Carrera M, Schofield PN, et al. (1994): Mosaic uniparental disomy in Beckwith-Wiedemann syndrome. J Med Genet 31:749-753.
- Schneid H, Suerin D, Vazquez MP, Gourmelen M, Cabrol S, et al. (1993): Parental allele specific methylation of the human insulin-like growth factor II gene and Beckwith-Wiedemann syndrome. J Med Genet 30:353-362.
Citation: Elawady H, Ragab T (2017) Hemihypertrophy Spectrum. J Bone Res 5:186. Doi: 10.4172/2572-4916.1000186
Copyright: © 2017 Elawady H, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Select your language of interest to view the total content in your interested language
Share This Article
International Conference on Emergency & Acute Care Medicine August 22-23, 2018 Tokyo, Japan
August 22-23, 2018 Tokyo, Japan
14th International Conference on Clinical Gastroenterology and Hepatology August 29-30, 2018 Toronto, Ontario, Canada
August 29-30, 2018 Toronto, Canada
World Conference on Neurology and Neuromuscular Disorders September 13-14, 2018 Frankfurt, Germany
September 13-14, 2018 Frankfurt, Germany
9th International Conference on Clinical & Medical Case Reports September 17-18, 2018 | Amsterdam, Netherlands
September 17-18, 2018 Amsterdam, Netherlands
World Congress on Fetal and Maternal Medicine October 15-17, 2018 Osaka, Japan
October 15-17, 2018 Osaka, Japan
Complementary & Alternative Medicine October 17-18, 2018 Las Vegas | Nevada | USA
October 17-18, 2018 Las Vegas, USA
11th International Conference on Clinical and Medical Case Reports October 22-23, 2018 Turkey
October 22-23, 2018 Istanbul, Turkey
- Total views: 2200
- [From(publication date): 0-2017 - Aug 16, 2018]
- Breakdown by view type
- HTML page views: 2142
- PDF downloads: 58