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Central nervous system: Paediatric and neurodevelopmental disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
Microcephaly may result from a variety of intrauterine factors. Congenital infections include TORCH (an acronym for toxoplasma, rubella, cytomegalovirus, herpes and other, now including the Zika virus), and there are chemical teratogens to enquire about and maternal phenylketonuria to consider. It may also be part of many genetic malformation syndromes, including the more severe autosomal trisomies and deletions, and is a striking feature of the autosomal recessive Seckel syndrome. Another important diagnosis to be considered is the very variable autosomal recessive Smith-Lemli-Opitz syndrome. Occasional mild forms of microcephaly inherited as a dominant trait have been recorded. Isolated severe microcephaly with a normal facial structure is often inherited as an autosomal recessive; the overall recurrence risk has been 10%–20% in different studies. Numerous specific genes have now been identified. Where no specific cause can be found, a recurrence risk of 10%–15% is appropriate, but a risk of close to 25% should be used if consanguinity is present.
Metabolic Diseases
Published in Stephan Strobel, Lewis Spitz, Stephen D. Marks, Great Ormond Street Handbook of Paediatrics, 2019
Stephanie Grünewald, Alex Broomfield, Callum Wilson
Smith–Lemli–Opitz syndrome (SLO) patients usually display characteristic dysmorphic features (Figs 14.34, 14.35) including syndactyly of the 2nd and 3rd toe, hypospadia and structural visceral and neurological abnormalities. There is usually global developmental delay with very slow progression of development. Challenging behaviour and sleeping difficulties can be a major task for families looking after these patients.
Individual conditions grouped according to the international nosology and classification of genetic skeletal disorders*
Published in Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow, Fetal and Perinatal Skeletal Dysplasias, 2012
Christine M Hall, Amaka C Offiah, Francesca Forzano, Mario Lituania, Michelle Fink, Deborah Krakow
Differential diagnosis:warfarin embryopathy is deemed to be a phenocopy of CDPX1, and generally also presents with cerebral and internal organ haemorrhages. A phenotype similar, although much more complex and severe than CDPX1 is described in multiple sulphatase defficiency, a recessive condition caused by mutations in the sulphatase-modifying factor-1 gene (SUMF1), responsible for the activation of all the sulphatase enzymes in the cell. CHILD syndrome is an acronym for Congenital Hemidysplasia with Ichthyosiform erythroderma and Limb Defects and is allelic to CDPX2, although it can also be caused by mutations in the gene NSDHL (NAD(P)H steroid dehydrogenase-like protein gene). It is a rare condition which shows unilateral involvement and a wide range of organ malformations (cardiac, genitourinary, endocrine, cerebral). The affected side has joint contractures and hypoplastic to aplastic limbs. The main differential diagnosis of RCDP is Zellweger syndrome (p. 301). Smith-Lemli-Opitz syndrome is a complex syndrome caused by a defect in the enzyme 3 beta-hydroxysterol-delta 7-reductase, which converts 7-dehydrocholesterol to cholesterol (gene DHCR7). Findings include dysmorphic features (bitemporal narrowing, ptosis, broad nasal bridge, short nasal root, anteverted nares, micrognathia), cleft palate and brain (microcephaly, corpus callosum agenesis, holoprosencephaly), genital, cardiovascular and gastrointestinal system anomalies. Skeletal anomalies include rhizomelia, postaxial polydactyly, syndactyly of second and third toes, short and proximally placed thumbs. Keutel syndrome is a rare, recessive disorder characterised by diffuse and progressive calcification of cartilage, also including nose, auricles, respiratory tract, dysmorphic facial features and peripheral pulmonary stenosis. It is caused by mutations in the vitamin K-dependent matrix Gla protein (MGP). Stippling is occasionally present in mucolipidosis type 2 (I-cell disease) (p. 381), GM1 gangliosidosis, Cornelia de Lange syndrome (p. 454), trisomy 18 (p. 586); trisomy 21 and fetal exposure to hydantoins and alcohol. Maternal autoimmune disorders, particularly systemic lupus erythematosus (p. 297), maternal hyperemesis and Sjogren syndrome have been associated with fetal stippling. Stippling is occasionally present in neonatal hypothyroidism: osteopaenia, wormian bones, wide anterior fontanelle.
A spontaneous partially thrombosed ductal aneurysm presenting with left recurrent laryngeal nerve palsy
Published in Acta Oto-Laryngologica Case Reports, 2020
Abhilasha Goswami, Anandita Das
Aneurysm of ductus arteriosus: Aneurysm of the ductus arteriosus is a clinical entity with a reported incidence rate of 8% [5]. The true incidence is unclear as the definition of ductus arteriosus aneurysm is not precise, and also because many incidentally diagnosed ductus arteriosus aneurysms (detected by foetal or neonatal echocardiography) resolve spontaneously with ductal closure and thrombosis, without any clinically apparent sequelae [6]. Ductus arteriosus aneurysm most commonly presents in infancy [7], but has also been reported in adults [8]. In approximately one-fourth of all patients, an underlying disorder such as trisomy 13, trisomy 21, Smith–Lemli–Opitz syndrome, type IV Ehlers–Danlos syndrome, or Marfan’s syndrome is present [9,10]. Rarely, the ductus arteriosus aneurysm may present with symptoms of a thoracic mass, including left bronchial obstruction [11] and hoarseness due to left vocal cord paralysis from recurrent left laryngeal nerve impingement [12]. Although many have a benign course, surgical resection is indicated if there is functional compromise of adjacent structures, persistent patency of the ductus, thrombus that extends into adjacent vessels, evidence of thromboembolic events, or underlying connective tissue disease [7].
Association between altered lipid profiles and attention deficit hyperactivity disorder in boys
Published in Nordic Journal of Psychiatry, 2018
Changes in the lipid profile might be related to the structural and functional brain changes reported in ADHD patients. Cholesterol has significant interactions with proteins, which control embryonic development, and plays an important role in developmental pathways such as the SHH pathway, which has a role in formation of the brain. The SHH is a morphogen involved in the patterning of the nervous system and limbs, together with other transcription factors and secreted proteins [50]. The SHH is covalently modified with both palmitate and cholesterol and secreted as part of a lipoprotein complex that regulates brain morphogenesis through the patched/smoothened signaling system, during embryonic development. It is secreted from the notochord and ventral floor plate cells and forms a concentration gradient along the entire dorsal-ventral axis. Following covalent modification by cholesterol, the post-translational effect of the SHH is the establishment of a morphogenic SHH concentration gradient that moves from high ventral concentration to low dorsal region concentration. Intracellular cell signaling systems are affected by variations in the SHH gradient, which ultimately determine the expression of future cell types by the sequential induction of transcription factors in ventra progenitor cells [51]. One determinant of the eventual structure of the maturing brain is the formation of discrete cell precursor domains in the neural tube as a result of the SHH morphogenic front [52]. Experimental studies have shown that during late embryonic and postnatal brain development, SHH signaling regulates neural precursor and stem cell proliferation in dorsal neocortical, hippocampal, tectal, and cerebellar regions [53]. A loss of SHH processing in humans can result in the failure of midline brain structures to form appropriately, as evidenced in holoprosencephaly [54]. In patients with Smith–Lemli–Opitz syndrome (SLOS), which is an autosomal recessive disorder of cholesterol biosynthesis caused by mutations in the gene encoding 7-dehydrocholesterol reductase (DHCR7), the most common neuroimaging abnormality has been reported to be incomplete formation of midline structures including the corpus callosum and cerebellum [55]. Of note, one of the most common neuroimaging abnormalities in ADHD is a reduction in the corpus callosum and cerebellum size, which supports the aberrant connectivity hypothesis that ADHD is a disorder of connectivity, involving inter- and intrahemispheric communications with possible alterations of intracortical connections [56]. In both ADHD and SLOS, it is not known whether callosal hypoplasia results from a primary patterning defect or later dysfunction of neuronal cortical connectivity and axonal migration, or both.