Paula and Bobby
Parents of Lillie
Acrodysostosis 1 with or without Hormone Resistance; ACRDYS1
What is Acrodysostosis 1 with or without Hormone Resistance; ACRDYS1?
Acrodysostosis 1 with or without Hormone Resistance; ACRDYS1 is a rare disease. It is also known as Acrodysostosis - hormone resistance Adohr Arkless-Graham syndrome Maroteaux-Malamut syndrome Peripheral dysostosis.
Sometimes called peripheral dysostosis, this syndrome was given the name acrodysostosis by Maroteaux and Malamut (1969). The facial appearance is characteristic in that the nose is hypoplastic; it is short with a broad tip, which is often dimpled, and with anteverted nostrils. Hypertelorism and epicanthic folds occur frequently. The short stature is prenatal in onset and birth weight and length are around the 3rd centile. Development is usually slow but seldom severely so. The hands are characteristic in that they are short and broad with a trident configuration, similar to achondroplasia. The skin outgrows the skeleton and is therefore redundant over the hands and feet. The nails are short and broad. Radiologically the metacarpals and phalanges are short with cone-shaped epiphyses, and there is hyperplasia of the first ray of the foot. Hamanishi et al., (1993) reported a 35-year-old woman with the condition where there was significant spinal canal stenosis. Viljoen et al., (1991) have pointed out that stippled epiphyses may be a feature.
Some patients have in addition hormone resistance (PRKAR1A mutaions have found in this subset - Linglart et al., 2011)
Most cases are sporadic but occasional autosomal dominant families have been reported (Frey et al., 1982; Niikawa et al., 1978; Hernandez et al., 1991). Gorlin et al., (1990) consider this condition to be the same as Albright hereditary osteodystrophy. See also Steiner and Pagon (1992) and Davies and Hughes (1992) for further discussion on this point. Wilson et al., (1997), however, found no evidence for reduced Gs-alpha bioactivity in two patients and in addition could find no mutations in the Gs-alpha gene. Graham et al., (2001) also could find no Gs-alpha abnormality, either at the protein or the DNA level in two patients. These authors felt that the pattern of hand abnormalities in acrodysostosis is distinctive, and spinal stenosis is a significant complication, not seen in Albright hereditary osteodystrophy. The condition has now been mapped and mutations found in PDE4D (Michot et al., 2012, Lee et al., 2012). This encodes the cAMP-dependent regulatory subunit of protein kinase A.
Ueyama et al. (2017) described a male patient with acrodysostosis due to heterozygous missense mutation in the PRKAR1A gene. Clinical characteristics included low birth weight, short stature, hypothyroidism and recurrent otitis media. Dysmorphic features included midface hypoplasia, upturned nose and epicanthal folds. Affected individuals had brachydactyly. Laboratory findings were TSH and PTH resistance; ACTH and GH levels were normal. X-rays showed short metatarsals and metacarpals, cone shaped epiphyses of the phalanges, and delayed bone age.
Michot et. al. (2018) reported 27 acrodysostosis and 5 acroscyphodysplasia cases. Heterozygous mutations were identified in PDE4D (total 11 patients, 2 of them with acroscyphodysplasia) or PRKAR1A (total 9 patients, 3 of them with acroscyphodysplasia).
Among the acrodysostosis cases, 9 heterozygous PRKAR1A variants and 11 heterozygous PDE4D variants were identified. In the acroscyphodysplasia cases, 2 PDE4D variants were identified. Hormone resistance was observed in patients carrying PRKAR1A variants, but not in patients with PDE4D variants. Patients with PDE4D variants had characteristic facial features including midface hypoplasia with nasal hypoplasia and some degree of intellectual disability.
* This information is courtesy of the L M D.
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What gene changes cause Acrodysostosis 1 with or without Hormone Resistance; ACRDYS1?
The syndrome is inherited in the following inheritance pattern/s:
Autosomal Dominant - In the case of autosomal dominant inheritance, just one parent is the carrier of the gene mutation, and they have a 50% chance of passing it onto each of their children. Syndromes inherited in an autosomal dominant inheritance are caused by just one copy of the gene mutation.
In some cases, a genetic syndrome may be the result of a de-novo mutation and the first case in a family. In this case, this is a new gene mutation that occurs during the reproductive process.
OMIM Number - 101800 (please check the OMIM page for updated information)
The syndrome can be caused by mutations in the following gene/s location/s:
PRKAR1A - 17q24.2
PDE4D - 5q11.2-q12.1
What are the main symptoms of Acrodysostosis 1 with or without Hormone Resistance; ACRDYS1?
The typical symptoms of the syndrome are:
Hypertelorism, Mild postnatal growth retardation, Short phalanx of finger, Hydrocephalus, Hypoplastic vertebral bodies, Hypogonadism, Hypoplasia of the maxilla, Hypodontia, Hearing impairment, Depressed nasal bridge, Blue irides, Accelerated skeletal maturation, Broad nasal tip, Broad palm, Brachycephaly, Calvarial hyperostosis, Cone-shaped epiphyses of the phalanges of the hand, Dislocated radial head, Disproportionate short-limb short stature, Elevated circulating parathyroid hormone level, Neonatal epiphyseal stippling, Epicanthus, Dental malocclusion, Delayed eruption of teeth, Cryptorchidism, Anteverted nares, Intellectual disability, Long hallux, Mandibular prognathia, Narrow vertebral interpedicular distance, Irregular menstruation, Optic atrophy, Autosomal dominant inheritance, Melanocytic nevus, Strabismus, Short metatarsal, Short metacarpal, Spinal canal stenosis, Short palm, Scoliosis
How does someone get tested for Acrodysostosis 1 with or without Hormone Resistance; ACRDYS1?
The initial testing for Acrodysostosis 1 with or without Hormone Resistance; ACRDYS1 can begin with facial genetic analysis screening, through the FDNA Telehealth telegenetics platform, which can identify the key markers of the syndrome and outline the type of genetic testing needed. A consultation with a genetic counselor and then a geneticist will follow.
Based on this clinical consultation with a geneticist, the different options for genetic testing will be shared and consent will be sought for further testing.
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