James McGill

Mutations in ENPP1 are associated with 'idiopathic' infantile arterial calcification

Idiopathic infantile arterial calcification (IIAC; OMIM 208000) is characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. We analyzed affected individuals from 11 unrelated kindreds and found that IIAC was associated with mutations that inactivated ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). This cell surface enzyme generates inorganic pyrophosphate (PPi), a solute that regulates cell differentiation and serves as an essential physiologic inhibitor of calcification.

Functional performance in young Australian children with achondroplasia

Aim  The aim of this study was to determine population‐specific developmental milestones for independence in self‐care, mobility, and social cognitive skills in children with achondroplasia, the most common skeletal dysplasia.

Developmental milestones in infants and young australasian children with achondroplasia

Background: Achondroplasia, the most common form of chondrodysplasia (inherited skeletal dysplasia), is characterized by a significant delay in the development of communication and motor skills, particularly during the first 2 years. Although some information regarding timing of development for children with achondroplasia is available, no study has evaluated simultaneously the pattern of skill development across multiple key developmental areas. Method: This study used a retrospective questionnaire to quantify developmental data on milestone achievement. Twenty families of children with achondroplasia throughout Australia and New Zealand were asked to document age of acquisition for 41 gross motor, fine motor, and communication and feeding milestones. More than one half of the items assessed were milestones identified in the Australian State Government Personal Health Record Books. The results are compared with previously available information regarding development of motor skills by a cohort of American children with achondroplasia. Results: Although the results support previously reported delays in gross motor and communication skill development, fine motor development does not seem to be as delayed as previously suggested. Information on development of self-feeding skills is presented for the first time and occurs later in this group than the typically developing population. We describe 2 distinctive and previously unreported methods of transitioning between static positions commonly used by children with achondroplasia. Conclusion: Delays were reported across gross motor and communication and feeding skills but were not observed during development of fine motor skills. Additional information is also offered regarding a variety of unusual movement strategies demonstrated by young children with achondroplasia.

Development in Children with Achondroplasia: A Prospective Clinical Cohort Study.

Aim  Achondroplasia is characterized by delays in the development of communication and motor skills. While previously reported developmental profiles exist across gross motor, fine motor, feeding, and communication skills, there has been no prospective study of development across multiple areas simultaneously.

An integrated approach to management of Marfan syndrome caused by an FBN1 exon 18 mutation in an Australian Aboriginal family

To the Editor: Marfan syndrome (MFS) is a severe autosomal dominant trait affecting the cardiovascular system, eyes, skeleton, dura, lungs, skin, and integument (1), caused by mutations of the fibrillin 1 gene (FBN1) on chromosome 15 (2). Death frequently results from dissection or rupture of the ascending aorta. Patients may have subluxation of the lens, usually, bilaterally. Skeletal manifestations include long arms and legs, long fingers, scoliosis, and pectus deformities. Other complications include lumbosacral dural ectasia and susceptibility to pneumothorax, herniae, and striae. The prevalence of MFS may be as much as one in 3–5000 (1). The penetrance of MFS appears high, but there is extensive phenotypic variability among affected individuals, even within families (2, 3). We have studied a large family of European and Australian Aboriginal origin. Sixty-two individuals at risk of MFS have been examined clinically since 1993. As shown in Fig. 1a, 18 family members had no features of MFS. Seventeen people independently met the criteria for a diagnosis of MFS (1), and 13 met these criteria when family history was taken into account, including two (IV3 and IV8) without lens subluxation. Three children (V18, V29, and V33) had lens subluxation but no other signs of MFS. Several individuals had involvement of one or two systems. None of these could be given a diagnosis of MFS. Patients could not be assessed for the major criterion lumbosacral dural ectasia (4, 5), because of the lack of imaging facilities in the remote area where they were examined. A positive result for this test would permit a diagnosis of MFS in five individuals, three with subluxated lenses (V18, V29, and V33), one with skeletal and ocular involvement (V1), and one with a dilated aorta and skeletal involvement (V4). In V3, the presence of dural ectasia would be suggestive but not conclusive. Immunohistochemical staining of fibrillin (6) in fibroblast cultures (established from punch biopsies of forearm or abdomen skin) of four affected family members (IV3, IV6, IV7, and IV21) revealed significant abnormalities (Fig. 1b). In control fibroblasts, most of the fibrillin was located in the extracellular area. The fibres were long, smooth, and fine in appearance. In the four affected family members examined, most of the fibrillin was found within the cells. The limited amount of fibrillin in the extracellular matrix was disorganized and appeared clumped rather than fibrous. DNA was extracted from blood or cheek cells (7). Polymerase chain reaction amplification of DNA was performed according to the protocol of Research Genetics (Huntsville, AL). Microsatellites were scored independently by two observers blind to the diagnosis. A LOD score (8) of 3.21 at y of 0 for the FBN1 microsatellite marker (9) and 6.36 at y of 0 for marker CYP-19 (10) indicated that the disease was closely linked to or at the FBN1 gene. As shown in Table 1, affected family members were found to carry the FBN1 2 allele and the CYP-19 178 bp allele. Twenty-one exons of the FBN1 gene were examined for DNA variants by single-strand conformation (SSC) analysis (11, 12). A variant was found using DNA from exon 18 of IV20 and was present in all tested affected individuals but not in healthy relatives, unrelated spouses, or 34 unrelated MFS patients (Table 1). Exon 18 was amplified with unlabeled primers to obtain material for direct automated sequencing using a kit (Applied Biosystems Inc., Foster City, CA). Sequencing was performed with both the sense and antisense amplification primers. Exon 18 DNA of IV20 showed a transition that replaced adenine with guanine at nucleotide position 2262. This mutation converts tyrosine to cysteine at position 754 in the amino acid sequence (Y754C). Six other family members, who met the revised diagnostic Clin Genet 2004: 65: 66–69 Copyright # Blackwell Munksgaard 2004 Printed inDenmark. All rights reserved CLINICALGENETICS

Recent developments in the diagnosis of Marfan syndrome and related disorders

Marfan syndrome is a multisystem disorder of connective tissue that is inherited in an autosomal dominant fashion, and results from mutation of the FBN1 gene on human chromosome 15. There are a number of conditions of the connective tissue with a similar phenotype that can be confused with Marfan syndrome. Modifications of the diagnostic criteria have recently been published, facilitating the differentiation of Marfan syndrome from these conditions. It is still difficult to use modern genetic testing for diagnosis because Marfan syndrome can be caused by many different mutations in FBN1, a large gene with 65 coding segments, while mutations in other genes can cause overlapping phenotypes. Several clinical trials of drug therapy, including the antihypertensive drug losartan, are in progress.

Medical management of children with achondroplasia : evaluation of an Australasian cohort aged 0-5 years

Aims:  Achondroplasia is the most common form of osteochondrodysplasia and is associated with a number of life‐threatening complications. The complexity of the condition led to the development of Heath Supervision Guidelines published by the American Academy of Pediatrics in 1995 and revised in 2005. There remains limited population‐based information on utilisation of medical and therapy services for children with achondroplasia. Increased information regarding use of these services will assist in future service development.

Retinal hemorrhages associated with meningitis in a child with a congenital disorder of glycosylation

A 9-month old infant presented in a state of shock to a district hospital. She was subsequently referred to the regional tertiary hospital. On admission, bruises were noted on the vertex of the skull. Retinal hemorrhages were present on ophthalmological examination. CT scan of the brain showed poor grey–white matter differentiation with apparent frontoparietal fractures of the skull. Her case was subsequently referred to the relevant authorities as it was suspicious for nonaccident injury (NAI). Her condition deteriorated and she died the next day. Postmortem examination showed that the bruises on the vertex were caused by rapid widening of the sutures of the skull, caused by rising intracranial pressure. There was no skull fracture or evidence of trauma. Histological examination of the brain showed meningitis which had extended to the optic nerve sheath. Hemorrhages were noted in the retinas as well as the optic nerve sheath. An incidental congenital disorder of glycosylation (CDG) was diagnosed on brain histology and confirmed by metabolic tests. Retinal hemorrhages are known to occur in head injuries especially in association with NAI. In this case, suspicion of NAI was further augmented by the presence of apparent bruises on the head. The full postmortem examination showed no evidence of injuries and instead showed that the child was suffering from meningitis. Blood culture grew Group A Streptococcus pyogenes. The underlying mechanisms for such a presentation and the association with CDG are discussed.

Congenital disorder of glycosylation type Ia in a 6-year-old girl with a mild intellectual phenotype: two novel PMM2 mutations.

SummaryWe report two novel mutations in the PMM2 gene in a girl with congenital disorder of gylcosylation type Ia (CDG Ia) and a mild intellectual phenotype.

Nephrocalcinosis: A potential complication of bisphosphonate therapy in children

Although bisphosphonate therapy is effective in severe childhood osteoporosis, both short and long term side effects occur. We have treated a total of 124 children including those with severe Osteogenesis Imperfecta (OI) since 1998, and more recently, patients with other forms of osteoporosis (e.g. juvenile idiopathic osteoporosis or steroid induced) with serious fractures (e.g. vertebral crush fractures). All patients received intravenous pamidronate therapy. The protocols (Table 1) were those used at the Children’s Hospital at Westmead at that time. Our protocol included a dietary calcium assessment to ensure a dietary calcium intake of 1200 mg/day for at least 1 week after the initial infusion to prevent hypocalcaemia, a known complication of bisphosphonate therapy. Patients were prescribed calcitriol 0.25 mcg twice daily at the time of each pamidronate infusion and for 7 days post-infusion. We present four patients who developed nephrocalcinosis during intravenous pamidronate therapy. None of these patients had nephrocalcinosis prior to commencement of therapy.