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.

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.

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.

Macrodystrophia lipomatosa of foot involving great toe.

Macrodystrophia lipomatosa is a rare form of congenital disorder in which there is localized gigantism characterized by progressive overgrowth of all mesenchymal elements with a disproportionate increase in the fibroadipose tissues. The adipose tissue infiltration involves subcutaneous tissue, periosteum, nerves and bone marrow. Most of the cases reported have hand or foot involvement. Patient seeks medical help for improving cosmesis or to get the size of the involved part reduced in order to reduce mechanical problems. We report a case of macrodystrophia lipomatosa involving medial side of foot with significant enlargement of great toe causing concern for cosmesis and inconvenience due to mechanical problems. The X-rays showed increased soft tissue with more of adipose tissue and increased size of involved digits with widening of ends. Since the patient's mother did not want any surgical intervention he was educated about foot care and proper footwear design was suggested.

Gigantism of the lower limb in Klippel-Trenaunay syndrome: anatomy of the lateral marginal vein.

The Klippel-Trenaunay syndrome is a combination of venous and capillary malformations associated with soft tissue and/or bony limb hypertrophy, with or without lymphatic malformations. Although persistent foetal veins are rare, the persistence of the lateral marginal vein is a common association in this syndrome. It results in venous hypertension, which gives rise to venous varicosities, which are commonly seen in this syndrome. This is a case report of a 28-year-old man with Klippel-Trenaunay syndrome, with persistence of the lateral marginal vein, affecting his right lower limb. He was treated with an above-knee amputation. The amputated limb was dissected to demonstrate the anatomy of the lateral marginal vein. To the best of the authors' knowledge, the gross anatomy of the lateral marginal vein has not been previously reported.

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.

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.

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.

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.

Surgical treatment of macrodactyly in older children and adults.

PURPOSE: To introduce a surgical technique for the treatment of macrodactyly in older children and adults, to represent the degree of correction obtained by the procedure, and to give the functional results. METHODS: Two thumbs and 5 fingers of 5 patients aged 12 to 32 years (mean, 17.5 years) with macrodactyly had surgery. The amount of tissue sufficient to reconstruct a normal-sized digit was left attached with the neurovascular bundle on the concave side of the macrodactylic digit and complete excision of whatever remained was performed. This requires usually arthrodesis of the distal interphalangeal joint with bone shortening. The large skin fold created during bone shortening and remaining angulations at the proximal phalanx were corrected during a second procedure. The patients were evaluated for 3 to 9 years (mean, 5.4 years) after the surgery. The length and circumferences of the involved digits and their opposites were measured before surgery and during the last follow-up examination to calculate the differences between the involved and the healthy digits, which were documented. The degree of reduction was quantified and noted. Two-point discrimination tests and active range of motion of the joints were recorded as well. RESULTS: For the thumbs an average 37% of circumference and 15% of length were reduced and for the fingers an average 44% of circumference and 35% of length were reduced. Ranges of motion of the joints of the involved digits were the same or nearly the same as before surgery in all of the cases. Two-point discriminations at the pulp of the involved digits were found to be the same as presurgical values in all digits. CONCLUSIONS: The technique is precise and simplifies the planning of the surgery. Although the macrodactylic digits with angulation deformities required a subsequent surgery for corrections patients with marked macrodactyly of the digit without a very wide proximal phalanx and metacarpal gained most from this technique.

Advanced imaging in renal osteodystrophy of the oral and maxillofacial region.

Magnetic resonance imaging and computed tomography was performed in one and two patients, respectively, with renal osteodystrophy (ROD). Conventional radiographs clearly depicted the characteristics of ROD of the oral and maxillofacial region. CT and MRI did not add any more information.

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.

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.

Digital enlargement in tuberous sclerosis.

A 23-year-old woman with a medical history significant for tuberous sclerosis presented with symptoms of postpartum endometritis. Focal gigantism of the third digit of her right hand was incidentally noted and is reported to be a rare manifestation of tuberous sclerosis.