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Chudley-Rozdilsky Syndrome

Intellectual Disability - Myopathy - Short Stature - Endocrine Defect

Chudley-Rozdilsky syndrome (CRS) is a very rare multisystem disease. The only two patients ever described suffered from a congenital non-progressive myopathy of type multiminicore myopathy, severe mental retardation, short stature and facial anomalies, hypoplasia of the pituitary fossa and pituitary gland as well as hypogonadotropic hypogonadism resulting therefrom. Little is known about the etiology and pathogenesis of the disease. Treatment can only be supportive until new insights are gained.


Presentation

CRS has been described as a "complex dysmorphic syndrome" [1], but otherwise all data available stem from the single case report published by Chudley et al. in 1985 [2]. Non-progressive myopathy and intellectual disability are the hallmarks of CRS and are rarely observed concomitantly in other entities. The former manifests in form of facial and generalized weakness, bilateral ptosis, partial gaze palsy, and severe lumbar lordosis, and those are mostly present at birth. Indeed, neonates are hypotonic, so-called "floppy infants". Severe mental and growth retardation becomes apparent when the child fails to reach the corresponding developmental milestones. A child experiencing CRS may only grow to a short stature. Additional symptoms of CRS are borderline microcephaly, characteristic facial features - particularly anteverted ears, hypertelorism, antimongoloid palpebral slants, exotropia, a prominent nasal bridge, and a highly arched palate -, and hypogonadism. Secondary sex characteristics are hardly developed. One of the patients described by Chudley and colleagues was myopic and both had bilateral clinodactyly.

Short Stature
  • A child experiencing CRS may only grow to a short stature.[symptoma.com]
  • MalaCards based summary : Chudley Rozdilsky Syndrome, also known as multicore myopathy with mental retardation, short stature, and hypogonadotropic hypogonadism, is related to multicore myopathy with mental retardation, short stature, and hypogonadotropic[malacards.org]
  • Overview A very rare syndrome characterized mainly by mental retardation, muscle disease, short stature and endocrine defects.[checkorphan.org]
  • Homepage Rare diseases Search Search for a rare disease Intellectual disability-myopathy-short stature-endocrine defect syndrome Disease definition Intellectual disability-myopathy-short stature-endocrine defect syndrome is a rare congenital myopathy[orpha.net]
Progressive Mental Retardation
  • Mental retardation, progressive Progressive mental retardation [ more ] 0006887 Lumbar hyperlordosis Excessive inward curvature of lower spine 0002938 Myopathy Muscle tissue disease 0003198 Showing of 34 Last updated: 7/1/2019 If you need medical advice[rarediseases.info.nih.gov]
Pharyngitis
  • […] group comprise very rare forms of Nemaline myopathy with central nervous system involvement as well as the combination of "microcephaly, mental retardation, spasticity with hyperreflexia, cerebellar dysfunction, short stature, Hirschsprung's disease, pharyngeal[symptoma.com]
  • […] related female-limited epilepsy / Pearson syndrome / Pectus carinatum / PEHO syndrome / Pelger-Huet anomaly / Pelvic dysplasia arthrogryposis of lower limbs / Pendred syndrome / Pentalogy of Cantrell / Pentosuria / Periodic fever, aphthous stomatitis, pharyngitis[gennome.com]
High Arched Palate
  • arched palate * Delayed puberty * Wide set eyes * Lordosis * Long arms * Long legs * Mental retardation * Weak eye muscles Causes - Chudley Rozdilsky syndrome Not supplied.[checkorphan.org]
  • Facial anomalies may include microcephaly, thickening of the skull, hemifacial microsomia, enlarged frontal sinuses, microtia, atretic ear canal, hypertelorism, blepharoptosis, myopia, limited sagittal eye movements, high arched palate, and facial muscle[accessanesthesiology.mhmedical.com]
Lordosis
  • […] definition Intellectual disability-myopathy-short stature-endocrine defect syndrome is a rare congenital myopathy syndrome characterized by nonprogressive myopathy (manifesting with mild facial and generalized weakness, bilateral ptosis, and severe lumbar lordosis[orpha.net]
  • […] definitionIntellectual disability-myopathy-short stature-endocrine defect syndrome is a rare congenital myopathy syndrome characterized by nonprogressive myopathy (manifesting with mild facial and generalized weakness, bilateral ptosis, and severe lumbar lordosis[malacards.org]
  • They also suffered from severe lordosis, an abnormal curvature of the spine.[symptoma.com]
  • […] head * Short stature * Dislocated hip * Droopy eyelid * Ophthalmoplegia * Myopia * Small penis * Facial palsy * Thickened skull * Decreased body hair * Delayed bone age * Downslanted fissures * High arched palate * Delayed puberty * Wide set eyes * Lordosis[checkorphan.org]
Joint Limitation
  • Muscle degeneration Muscle wasting [ more ] 0003202 Sparse body hair 0002231 30%-79% of people have these symptoms Abnormality of the hip bone Abnormality of the hips 0003272 Limitation of joint mobility Decreased joint mobility Decreased mobility of joints[rarediseases.info.nih.gov]
Decrease in Height
  • […] body height Small stature [ more ] 0004322 Skeletal muscle atrophy Muscle degeneration Muscle wasting [ more ] 0003202 Sparse body hair 0002231 30%-79% of people have these symptoms Abnormality of the hip bone Abnormality of the hips 0003272 Limitation[rarediseases.info.nih.gov]
Osteopenia
  • Musculoskeletal anomalies may include delayed bone maturation, osteopenia, lumbar hyperlordosis, limited joint mobility (particularly of the big joints, e.g., shoulders, elbows, hips, knees, ankles), clinodactyly, and evidence of mild but generalized[accessanesthesiology.mhmedical.com]
  • […] with retinitis pigmentosa / Postnatal progressive microcephaly, seizures, and brain atrophy / Potassium aggravated myotonia / Potato nose / Potocki-Lupski syndrome / Potocki-Shaffer syndrome / Potter sequence / PPM-X syndrome / Prader-Willi habitus, osteopenia[gennome.com]
Long Arm
  • arms * Long legs * Mental retardation * Weak eye muscles Causes - Chudley Rozdilsky syndrome Not supplied.[checkorphan.org]
Alopecia
  • Contractures Dwarfism Mental Retardation Alopecia Epilepsy Oligophrenia Syndrome of Moynahan Alopecia, Epilepsy, Pyorrhea, Mental Subnormality Alopecia, Hypogonadism, Extrapyramidal Disorder Alopecia, Neurologic Defects, and Endocrinopathy Syndrome Alopecia-Mental[rgd.mcw.edu]
  • Alopecia hypogonadism extrapyramidal disorder 0 *Alopecia *Basal Ganglia Diseases *Hypogonadism. Woodhouse Sakati syndrome 0 *Alopecia *Arrhythmias, Cardiac *Diabetes Mellitus *Hypogonadism *Intellectual Disability.[reference.md]
  • Ichthyosis - alopecia - ecl... Jagell-Holmgren-Hofer syn... What do we feel? It's a rare disease which normally occurs either in the neonatal PHASE/PERIOD or in babyhood, 1 ... Ichthyosis - hepatosplenome... Dykes-Markes-Harper syndr...[aidweb.org]
  • […] epilepsy oligophrenia syndrome of Moynahan / Alopecia intellectual disability syndrome 2 / Alopecia macular degeneration growth retardation / Alopecia totalis - Not a rare disease / Alopecia universalis / Alopecia universalis onychodystrophy vitiligo[gennome.com]
Hypertelorism
  • Facial anomalies may include microcephaly, thickening of the skull, hemifacial microsomia, enlarged frontal sinuses, microtia, atretic ear canal, hypertelorism, blepharoptosis, myopia, limited sagittal eye movements, high arched palate, and facial muscle[accessanesthesiology.mhmedical.com]
  • Human phenotypes related to Multicore Myopathy with Mental Retardation, Short Stature, and Hypogonadotropic Hypogonadism: 60 33 (show all 35) # Description HPO Frequency Orphanet Frequency HPO Source Accession 1 hypertelorism 60 33 hallmark (90%) Very[malacards.org]
  • Additional symptoms of CRS are borderline microcephaly, characteristic facial features - particularly anteverted ears, hypertelorism, antimongoloid palpebral slants, exotropia, a prominent nasal bridge, and a highly arched palate -, and hypogonadism.[symptoma.com]
  • Delayed skeletal development [ more ] 0002750 Disproportionate tall stature 0001519 Downslanted palpebral fissures Downward slanting of the opening between the eyelids 0000494 Facial palsy Bell's palsy 0010628 Hyperlordosis Prominent swayback 0003307 Hypertelorism[rarediseases.info.nih.gov]
Prominent Nasal Root
  • nasal root Protruding bridge of nose Protruding nasal bridge [ more ] 0000426 Protruding ear Prominent ear Prominent ears [ more ] 0000411 5%-29% of people have these symptoms Abnormality of cardiovascular system morphology 0030680 Abnormality of the[rarediseases.info.nih.gov]
Spastic Quadriplegia
  • Quadriplegia, and Mental Retardation Ichthyosis-Mental Retardation Syndrome with Large Keratohyalin Granules in the Skin Iida Kannari Syndrome Iliotibial Band Syndrome IMAGe syndrome immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome[rgd.mcw.edu]

Workup

The non-progressive myopathy presented by CRS patients has been classified as multiminicore myopathy. In the 1980s, the diagnosis of this condition was based on the histological examination of tissue samples obtained by means of muscle biopsies. In detail, Chudley and colleagues observed a moderate variation of fiber diameters, numerous internally placed nuclei in about half of all fibers, atrophic type 1 muscle fibers, focal loss of cross striations and cores of myofibrillar disruption. Those cores were located eccentrically and perpendicular to the long axis of the muscle fiber. They were largely missing mitochondria. Neither necrotic foci nor infiltration of inflammatory cells have been noted. Affected muscle fibers didn't seem to regenerate and were neither replaced by fibrous tissue. Apparently healthy and degraded shares of the muscle fiber were separated by a well defined border [2].

Biochemical analyses and diagnostic imaging may be employed to confirm hypogonadotropic hypogonadism and to determine the state of skeletal development. Blood counts yield normal results, but serum concentrations of gonadotropins, testosterone and estradiol in men and women, respectively, are below reference ranges. A generalized retardation in skeletal maturation has been observed in both patients. Growth plate fusion is significantly delayed. Also worth mentioning are the typically small cranial vault and pituitary fossa [2].

Molecular biological studies are highly recommended in case of suspected CRS to fill existing knowledge gaps regarding the etiology of the disease. While gene panel sequencing may be a good starting point, a more comprehensive approach would be required to identify possible sequence anomalies that have not been yet related to congenital myopathy, mental retardation and combinations thereof [3]. Whole-exome sequencing is likely to yield interesting results and is less cost-intensiv than whole-genome sequencing [3].

Delayed Bone Age
  • bone age * Downslanted fissures * High arched palate * Delayed puberty * Wide set eyes * Lordosis * Long arms * Long legs * Mental retardation * Weak eye muscles Causes - Chudley Rozdilsky syndrome Not supplied.[checkorphan.org]

Treatment

Causal treatment is not available. Patients could most likely benefit from a tailor-made, multidisciplinary approach to therapy that comprises regular physiotherapy, the provision of orthopedic devices, hormone replacement therapy, and dietary supplementation. Surgical interventions may be considered.

Due to their severe intellectual disability, CRS patients require the attention of professionals in alternative educational institutions [4]. Also, parents and possibly other family members should receive psychological support.

Prognosis

Even though motor impairments, skeletal anomalies and mental retardation as well as additional symptoms reduce life quality, CRS patients have been shown to live well into adulthood [2]. Little can be stated at present regarding their overall life expectancy, but life-threatening complications of the disease have not been described. It is remarkable that CRS patients don't seem to experience significant respiratory muscle weakness, while those suffering from typical multiminicore myopathy often do [1].

Etiology

Both patients known to have suffered from CRS, a man and a woman, were children of a cousins, i.e., of third-degree relatives. Neither parent showed any symptoms of CRS. This also applies to four siblings of the affected individuals, although one of them and a distant relative proved to be intellectually disabled [2]. These facts argue in favor of an autosomal recessive inheritance pattern. Possibly, sequence anomalies as those observed in multiminicore myopathy may have accounted for the disease. A multigenic origin of CRS may also be presumed, but appears less likely due to the high phenotypic consistency between both patients and the near-total absence of CRS-related symptoms in their siblings. In the end, the current state of knowledge does not allow for any reliable statements to this end.

Epidemiology

Only a single case report of CRS has ever been published [2]. This syndrome is one of the few conditions in which congenital myopathies are not restricted to the skeletal muscle [4]. Other conditions pertaining to that group comprise very rare forms of Nemaline myopathy with central nervous system involvement [5] as well as the combination of "microcephaly, mental retardation, spasticity with hyperreflexia, cerebellar dysfunction, short stature, Hirschsprung's disease, pharyngeal web, and facial dysmorphism" described in a case report by Kim et al. [6].

While the overall prevalence of congenital myopathies has been estimated to 1 in 26,000 people in the United States [7] and to 1 in 50,000 individuals aged over five years in Denmark [8], the prevalence of multiminicore myopathy is presumed to be much lower. Most commonly, multiminicore myopathy results from mutations in the gene encoding for the skeletal muscle ryanodine receptor [9]. Regarding those mutations, a heterozygous mutation carrier frequency of 1 in 2,000 persons has been determined in the Japanese population [10]. Thus, the likelihood of both parents of a child being such carriers is as low as 1 in 4,000,000. The prevalence of CRS can only be described as anectodically [4].

The patients described by Chudley et al. were brother and sister [2]. Thus, it can be concluded that CRS may affect people of both genders.

Sex distribution
Age distribution

Pathophysiology

Virtually nothing is known about the etiology of the disease and thus, the pathophysiological events leading to the complex clinical picture remain elusive.

Prevention

Affected families might benefit from genetic counseling if the identification of the causal mutation was achieved. Precise knowledge regarding the etiology of the disease would also allow for an early diagnosis during pregnancy. Considering what is known to date about CRS, a prenatal diagnosis seems highly unlikely: Growth retardation is not to be expected in utero, leaving reduced fetal movements as the only, yet unspecific clue towards the disease [11].

Summary

In 1985, Chudley and colleagues published a case report titled "Multicore disease in sibs with severe mental retardation, short stature, facial anomalies, hypoplasia of the pituitary fossa, and hypogonadotrophic hypogonadism" [2]. This presumably genetic disorder hadn't been described before and has subsequently been named CRS.

The affected siblings were children of a consanguineous couple and suffered from a congenital, non-progressive myopathy associated with generalized weakness that has been diagnosed as multicore myopathy after the affected individuals reached adulthood [2]. Today, the term multiminicore myopathy is preferred over the term of multicore myopathy, and while this type of myopathy is known to be inherited in an autosomal recessive manner, it is not usually associated with neurological and endocrinological disorders as those described by Chudley et al. Multiminicore myopathy has repeatedly been related to central core myopathy and malignant hyperthermia, though [11] [12]. It may result from mutations in the genes encoding for the skeletal muscle ryanodine receptor (RYR1) or for selenoprotein N (SELN).

As can be inferred from the title given above, CRS encompasses mental retardation and developmental disturbances affecting the pituitary fossa and the pituitary gland, which lead to hypogonadotrophic hypogonadism, then still named "sexual infantilism". Although Chudley and colleagues carried out cytogenetic studies, they found little more than a few disperse anomalies whose accumulation was probably due to consanguineous relationships within the family. No chromosomal aberration could clearly be related to the observed phenotype [2]. To date, the genetic cause of CRS remains unclear. Although it may be speculated that CRS results from SELN or RYR1 mutations combined with mutations in other genes, this hypothesis cannot currently be proven or refuted.

Patient Information

Chudley-Rozdilsky syndrome (CRS) is a very rare disease that has only been described in two patients, one boy and one girl. In detail, Chudley, Rozdilsky and their colleagues published a case report about two siblings suffering from a non-progressive myopathy, severe mental retardation, short stature and facial anomalies, skeletal defects and an impaired sexual development. Both were born as floppy infants, i.e., they presented with marked muscle hypotonia at birth. Furthermore, those neonates showed unusual facial features, namely widely divergent eyes with slanting palpebral fissures, drooping upper eyelids, a prominent nasal bridge, and a highly arched palate. During early development, severe mental and growth retardation became apparent. Both grew to a final height of 140-150 cm and achieved an IQ of approximately 20. They also suffered from severe lordosis, an abnormal curvature of the spine. Even after adolescence, their genitals remained childlike, and they hardly developed secondary sex characteristics such as axillary and pubic hair, and breast growth in the female patient.

At the time of diagnosis, the patients were 25 and 38 years old. Nothing indicated they had a shorter-than-normal life expectancy, but the subsequent evolution of their disease has not been made public. The origin of CRS remain unknown, although it seems likely the disease is inherited in an autosomal recessive manner. Children of consanguineous couples are thus more likely to experience CRS. Due to significant knowledge gaps regarding the causes of the disease, treatment can and was mainly supportive. Affected individuals could benefit from regular physiotherapy, the provision of orthopedic devices, hormone replacement therapy, and dietary supplementation, their families from psychological support.

References

Article

  1. Jungbluth H. Multi-minicore Disease. Orphanet J Rare Dis. 2007; 2:31.
  2. Chudley AE, Rozdilsky B, Houston CS, Becker LE, Knoll JH. Multicore disease in sibs with severe mental retardation, short stature, facial anomalies, hypoplasia of the pituitary fossa, and hypogonadotrophic hypogonadism. Am J Med Genet. 1985; 20(1):145-158.
  3. Hunter JM, Ahearn ME, Balak CD, et al. Novel pathogenic variants and genes for myopathies identified by whole exome sequencing. Mol Genet Genomic Med. 2015; 3(4):283-301.
  4. Astrea G, Battini R, Lenzi S, et al. Learning disabilities in neuromuscular disorders: a springboard for adult life. Acta Myol. 2016; 35(2):90-95.
  5. Ryan MM, Schnell C, Strickland CD, et al. Nemaline myopathy: a clinical study of 143 cases. Ann Neurol. 2001; 50(3):312-320.
  6. Kim JJ, Armstrong DD, Fishman MA. Multicore myopathy, microcephaly, aganglionosis, and short stature. J Child Neurol. 1994; 9(3):275-277.
  7. Amburgey K, McNamara N, Bennett LR, McCormick ME, Acsadi G, Dowling JJ. Prevalence of congenital myopathies in a representative pediatric united states population. Ann Neurol. 2011; 70(4):662-665.
  8. Witting N, Werlauff U, Duno M, Vissing J. Phenotypes, genotypes, and prevalence of congenital myopathies older than 5 years in Denmark. Neurol Genet. 2017; 3(2):e140.
  9. Lillis S, Abbs S, Ferreiro A, Muntoni F, Jungbluth H. Clinical utility gene card for: Multi-minicore disease. Eur J Hum Genet. 2012; 20(2).
  10. Wu S, Ibarra MC, Malicdan MC, et al. Central core disease is due to RYR1 mutations in more than 90% of patients. Brain. 2006; 129(Pt 6):1470-1480.
  11. Klaska C, Gonik B. Obstetric outcome in a primigravid patient with autosomal-recessive multiminicore myopathy. Obstet Gynecol. 2014; 123(2 Pt 2 Suppl 2):438-440.
  12. Mathews KD, Moore SA. Multiminicore myopathy, central core disease, malignant hyperthermia susceptibility, and RYR1 mutations: one disease with many faces? Arch Neurol. 2004; 61(1):27-29.

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Last updated: 2019-07-11 20:24