Nonisolated diaphragmatic hernia in Simpson-Golabi-Behmel syndrome.

OBJECTIVE: Congenital diaphragmatic hernia (CDH) is associated with Simpson-Golabi-Behmel syndrome (SGBS), but few cases diagnosed prenatally have been reported. The aim of this series is to highlight the association of nonisolated CDH with SGBS type I on prenatal ultrasound and emphasize the importance of genetic testing, fetal autopsy, and family history in confirming this diagnosis. METHOD: Retrospective review of 3 cases of SGBS type I in a single tertiary care centre. Family history, fetal ultrasound, autopsy findings, and genetic testing for GPC3 was performed for each case. RESULTS: Fetal ultrasound findings in the second trimester were CDH, omphalocele, increased nuchal fold, renal anomaly, and cleft lip and palate. Fetal autopsy confirmed the prenatal ultrasound findings and also showed dysmorphic facial features and premalignant lesions on renal and gonadal histology. Microarray and DNA analysis of the GPC3 gene confirmed the diagnosis of SGBS type I in each case. CONCLUSION: Nonisolated CDH in a male fetus suggests a diagnosis of SGBS type I. Fetal autopsy, pedigree analysis, and genetic testing for GPC3 are all essential to confirming the diagnosis. The histological findings of ovotestes and nephroblastomatosis indicate that cancer predisposition is established early in fetal life.

Prenatal case of Simpson-Golabi-Behmel syndrome with a de novo 370Kb-sized microdeletion of Xq26.2 compassing partial GPC3 gene and review.

BACKGROUND: Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is a rare X-linked recessive disorder characterized by pre- and postnatal overgrowth and a broad spectrum of anomalies including craniofacial dysmorphism, heart defects, renal, and genital anomalies. Due to the ultrasound findings are not pathognomonic for this syndrome, most clinical diagnosis of SGBS1 are made postnatally. METHODS: A pregnant woman with abnormal prenatal sonographic findings was advised to perform molecular diagnosis. Single nucleotide polymorphism array (SNP array) was performed in the fetus, and the result was validated with multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR (qPCR). RESULTS: The prenatal sonographic presented with increased nuchal translucency at 13 gestational weeks, and later at 21 weeks with cleft lip and palate, heart defect, increased amniotic fluid index and over growth. A de novo 370Kb-deletion covering the 5'-UTR and exon 1 of GPC3 gene was detected in the fetus by SNP array, which was subsequently confirmed by MLPA and qPCR. CONCLUSION: The de novo 370Kb hemizygous deletion of 5'-UTR and exon 1 of GPC3 results in the SGBS1 of this Chinese family. Combination of ultrasound and genetics tests helped us effectively to diagnose the prenatal cases of SGBS1. Our findings also enlarge the spectrum of mutations in GPC3 gene.

Sotos syndrome: antenatal presentation.

There is little published information regarding the clinical presentation of Sotos syndrome in pregnancy. In this report, we describe the antenatal presentation of a child subsequently diagnosed with Sotos syndrome by molecular analysis. The pregnancy was complicated by a positive maternal serum screen and abnormal ultrasound findings including macrocephaly, polyhydramnios and decreased fetal movements. This is the first report of an elevated Down syndrome risk in a pregnancy with confirmed Sotos syndrome. Sotos syndrome should be included in the differential diagnosis of newborns with a normal karyotype where the pregnancy has demonstrated an increased risk for Down syndrome by maternal serum screening, especially in the presence of supportive ultrasound findings.

Case study of a 15-year-old boy with McCune-Albright syndrome combined with pituitary gigantism: effect of octreotide-long acting release (LAR) and cabergoline therapy.

The use of octreotide-LAR and cabergoline therapy has shown great promise in adults with acromegaly; however, the experience in pediatric patients has rarely been reported. We described a clinical course of a 15-year-old boy of McCune-Albright syndrome (MAS) with pituitary gigantism. At the age of 8 years, a growth hormone (GH) and prolactin (PRL) producing pituitary adenoma was diagnosed at our hospital. He also had multiple fibrous dysplasia, so that he was diagnosed as having MAS. The tumor was partially resected, and GNAS1 gene mutation (R201C) was identified in affected tissues. We introduced octreotide to suppress GH secretion (100 mug 2/day s.c). During therapy with octreotide, IGF-1 and GH levels could not be suppressed and the patient frequently complained of nausea from octreotide treatment. Therefore, the therapy was changed to monthly injections of octreotide-LAR at the age of 12.3 years and was partially effective. However, as defect of left visual field worsened due to progressive left optic canal stenosis, he underwent second neurological decompression of the left optic nerve at 13.4 years of age. After surgery, in addition to octreotide-LAR, cabergoline (0.25 mg twice a month) was started. This regimen normalized serum levels of GH and IGF-1; however, he showed impaired glucose tolerance and gallstones at 15.7 years of age. Therefore, the dose of octreotide-LAR was reduced to 10 mg and the dose of cabergoline increased. This case demonstrated the difficulty of treating pituitary gigantism due to MAS. The use of octreotide-LAR and cabergoline should be considered even in pediatric patients; however, adverse events due to octreotide-LAR must be carefully examined.

Somatic GPR101 Duplication Causing X-Linked Acrogigantism (XLAG)-Diagnosis and Management.

CONTEXT: Recent reports have proposed that sporadic or familial germline Xq26.3 microduplications involving the GPR101 gene are associated with early-onset X-linked acrogigantism (XLAG) with a female preponderance. CASE DESCRIPTION: A 4-year-old boy presented with rapid growth over the previous 2 years. He complained of sporadic headaches and had coarse facial features. His height Z-score was +4.89, and weight Z-score was +5.57. Laboratory testing revealed elevated serum prolactin (185 µg/L; normal, <18 µg/L), IGF-1 (745 µg/L; normal, 64-369 µg/L), and fasting GH > 35.0 µg/L. Magnetic resonance imaging demonstrated a homogenous bulky pituitary gland (18 × 15 × 13 mm) without obvious adenoma. A pituitary biopsy showed hyperplastic pituitary tissue with enlarged cords of GH and prolactin cells. Germline PRKAR1A, MEN1, AIP, DICER1, CDKN1B, and somatic GNAS mutations were negative. Medical management was challenging until institution of continuous sc infusion of short-acting octreotide combined with sc pegvisomant and oral cabergoline. The patient remains well controlled with minimal side effects 7 years after presentation. His phenotype suggested XLAG, but his peripheral leukocyte-, saliva-, and buccal cell-derived DNA tested negative for microduplication in Xq26.3 or GPR101. However, DNA isolated from the pituitary tissue and forearm skin showed duplicated dosage of GPR101, suggesting that he is mosaic for this genetic abnormality. CONCLUSIONS: Our patient is the first to be described with somatic microduplication leading to typical XLAG phenotype. This patient demonstrates that a negative test for Xq26.3 microduplication or GPR101 duplication on peripheral blood DNA does not exclude the diagnosis of XLAG because it can result from a mosaic mutation affecting the pituitary.

Proteus syndrome: a rare cause of hemihypertrophy and macrodactyly on bone scanning.

Proteus syndrome is a rare, sporadic genetic disorder characterized by overgrowth of multiple different tissues in a mosaic pattern. It is associated with connective tissue nevi, epidermal nevi, disproportionate overgrowth of multiple tissues, vascular malformations, characteristic tumors, and specific facial anomalies. Joseph Merrick, popularly known as the Elephant Man, is now believed to have suffered from Proteus syndrome. A case of Proteus syndrome and associated findings on bone scintigraphy are presented.

Congenital macrodactyly: a clinical study.

Congenital macrodactyly is a rare congenital malformation characterised by progressive enlargement of all mesenchymal elements of a digit. The present study is an attempt to draw the attention towards the similarities and differences between macrodactyly of the hand and foot. Radiographical, operative findings and histopathological examination of five cases are included in the present study. Emphasis was given to know the possible basic lesion. Radiographic findings, which differentiate this entity from other forms of local gigantism, were also analysed. The most characteristic finding noted was excessive overgrowth of fibro-fatty tissue with unusually large fatty lobules, apparently fixed by a mesh of dense fibrous tissue. Hypertrophy and tortuosity of the digital nerve, a striking feature in macrodactyly of the hand, was notably absent in cases affecting the foot. None of the patients had any other associated congenital anomalies. Neither the patients nor any of their family members had any stigmata of neurofibromatosis. Chromosomal study was normal in all of them. We conclude that in macrodactyly of the foot, excessive proliferation and accumulation of adipose tissue was the basic lesion, whereas involvement of the nerve might be the fundamental lesion in gigantism of the hand. Furthermore, whatever be the basic lesion, the final pathway must be either the local deficiency of a growth inhibiting factor or local expression of a basic intrinsic factor, leading to excessive growth of all elements of the digit.

Metacarpophalangeal pattern profile analysis in Sotos syndrome.

The metacarpophalangeal pattern profile (MCPP) was analyzed on 16 Sotos syndrome patients. A mean Sotos syndrome profile was produced. Correlation studies confirm clinical homogeneity of Sotos syndrome individuals. Discriminant analysis of Sotos syndrome patients and normal individuals produces a function of two MCPP variables and age, which may provide a useful tool for diagnosis.

Metacarpophalangeal pattern profile analysis in Sotos and Marfan syndrome.

Patients with Sotos and Marfan syndrome have unusually long metacarpals and phalanges which may make the differential diagnosis difficult in younger children. Using Q-scores, we compared metacarpophalangeal pattern profile (MCPP) analysis in these two syndromes and identified distinct and different pattern profiles. This illustrates that the MCPPs are specific in these syndromes, even at an early age, and not related solely to the unusually long metacarpals and phalanges. For this study we used data from 50 Sotos patients (34 from the United Kingdom and 16 from the Netherlands, with a total of 95 hand films) and 36 Marfan patients (from the Netherlands, with 98 hand films). Of all patients over age 3 years the bone length (including the epiphysis) was determined. The patients under 7 1/2 years (29 Sotos and 12 Marfan) were also measured without inclusion of the epiphysis. The patients measured without epiphysis had a relative short metacarpal 1 (MC1) and long distal phalanx 1 (DPh1) in Sotos syndrome, and a relative long MC1 and short DPh1 in Marfan syndrome. Between age 3 and 7 1/2 years more than 90% of the films could be classified correctly using these two variables. Of the roentgenograms measured with epiphyses, about 80% were classified correctly.

McCune-Albright syndrome: clinical and molecular evidence of mosaicism in an unusual giant patient.

Molecular genetics recently uncovered the mystery of the protean picture of McCune-Albright syndrome by identification of the somatic gain of function mutations in the GNAS1 gene. Here we present an adult patient with fibrous dysplasia and an endocrinopathy resulting in unusual giant height. The clinical diagnosis in the patient could be confirmed by molecular investigations in tissues involved in the process of fibrous dysplasia.

Macrodystrophia lipomatosa: radiographic observations.

23 cases of macrodystrophia lipomatosa (MDL) are reported showing a wide spectrum of radiographic findings. Typical findings were hypertrophy of all the mesodermal tissues of the affected digits with dramatic overgrowth of fat. Phalanges were enlarged both in length and transverse diameter, but the trabecular pattern was maintained. In one patient, the phalanges and metatarsals were elongated but thinned. In another case, all the phalanges and metatarsals of the great toe were small. The little toe was also involved in two cases. Articular surfaces were slanting. There was a high incidence of palmar and plantar involvement. In a few cases the forearm and leg were also involved. Other uncommon features observed were early maturation of epiphyseal centres of ossification of phalanges and metatarsals, syndactyly, polydactyly, brachydactyly and symphalangism. Angiography was uncharacteristic.

Cerebral gigantism (Sotos' syndrome). Metacarpophalangeal pattern profiles.

The metacarpophalangeal pattern (MCPP) profile in 17 out of 22 patients with Sotos' syndrome was studied throughout the growth period, from 2 weeks to 19 years of age. Two typical MCPP profiles will be described. The first type of profile was found in 13 patients. Although the form of the profile is the same throughout the years, the lengthening of the fingers is most pronounced around 2 years of age. Before and after that period there is a flattening of the curve. The metacarpals are relatively longer below the age of 3 years, above 3 years the lengthening of the proximal phalanges is more pronounced in the profile. The second type of profile was found in 4 patients. This curve is almost a mirror image of the first profile. The fingers are not as long as in the first type and the profile is less pronounced. In one of the 17 patients the transition from the first type to the second type could be demonstrated. One patient had a normal profile.

Macrodystrophia lipomatosa: CT and MR findings.

Macrodystrophia lipomatosa is a congenital macrodactyly characterized by proliferation of all mesenchymal components, particularly fibroadipose tissue. We report imaging features of two such patients. MR imaging and CT scanning demonstrated proliferation of fatty tissue in the territory of the median nerve in the hands and forearms, characteristic of macrodystrophia lipomatosa.

Macrodystrophia lipomatosa of the foot: a report of three cases and literature review.

Macrodystrophia lipomatosa is a distinct clinical entity often misdiagnosed as other forms of macrodactyly. The most specific finding is an overabundance of fibrofatty tissue on the plantar aspect of the foot. Three cases, with the diagnoses made from tissue specimens, are presented in this article. The clinical, pathologic, and roentgenographic findings are discussed and a review of the literature is provided.

Progressive pedal macrodactyly surgical history with 15 year follow-up.

Macrodactyly can affect the fingers and/or toes1. Histopathologic examination will distinguish macrodactylia fibrolipomatosis or neural fibrolipoma with macrodactyly, from macrodactylia as a part of neurofibromatosis. Surgical repair is aimed at decreasing the size of the affected foot so it is as near in size and shape to the normal foot as possible. Surgical approaches have included reconstructive surgery (usually staged debulking procedures), epiphyseal plate arrest and amputation. Repeated reconstructive surgical procedures, as illustrated in this report covering patient care over a 15 year period, are usually necessary due to recurring soft tissue and boney enlargement.

Sotos syndrome presenting with epilepsy.

A fourteen and a half year-old boy of tall stature presenting with epilepsy was diagnosed as having Sotos syndrome (cerebral gigantism) at the Hacettepe University Children's Hospital. Since EEG abnormalities are known manifestations in this syndrome, a case presenting with epilepsy is very rare. We believe that a presumed cerebral defect could create convulsions and would thus be the cause of cerebral gigantism whose etiology is still unclear. Thus patients with this syndrome should be followed up for the risk of epilepsy.

Overgrowth syndromes.

The causes of these fascinating conditions and the mechanisms by which infants of such proportions are formed remain generally unknown. Future understanding of the overgrowth syndromes is likely to be gained from studies employing the exciting new methodology of molecular genetics.

Macrodystrophia lipomatosa. A case report.

Macrodystrophia lipomatosa, a rare form of localized gigantism of unknown cause, is characterized by a dramatic overgrowth of all the mesenchymal elements, particularly the fibroadipose tissue, of one or more digits of the foot or hand. Of the known forms, static and progressive (1), we report the case of an African patient, of Bantu origin, who had a progressive deformity of his left hand.