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Pseudopseudohypoparathyroidism

Pseudo Pseudohypoparathyroidism

Pseudopseudohypoparathyroidism is a very rare autosomal dominant genetic disorder that is considered to be a variant of Albright's hereditary osteodystrophy. Transmission of GNAS mutations from the father is the mechanism of the disease. Typical findings include short stature, obesity, round facies, and reduced length of metacarpal and metatarsal bones, but without resistance to parathyroid hormone (PTH), which is one of the main biochemical clues in the diagnosis of pseudopseudohypoparathyroidism. A positive family history and subsequent genetic studies are vital for confirming the diagnosis.


Presentation

Pseudopseudohypoparathyroidism (PPHP), a very rare disorder initially described more than 50 years ago, stems from a genetic phenomenon known as "genomic imprinting", where the expression of mutated genes differs for maternal and paternal transmission [1] [2] [3]. Namely, PPHP is a subtype of Albright's hereditary osteodystrophy (AHO), an autosomal dominant disease that develops due to mutations of the genes encoding the α subunit of the Gs protein (GNAS1) located on chromosome 20 [1] [4]. If this mutation is transferred from the chromosome of the mother, pseudohypoparathyroidism (PHP) type 1a will develop, but if paternal transmission occurs, children suffer from pseudopseudohypoparathyroidism [1] [5] [6] [7] [8]. The clinical presentation is practically identical for both forms - a short stature with reduced growth of metacarpal and metatarsal bones (manifesting as shorter fingers and toes, or brachydactyly), as well as obesity and a round face [1] [4]. However, the distinguishing feature of PPHP is normal circulating levels of parathyroid hormone (PTH) and its unchanged activity in the kidneys, which in the case of PHP leads to hypocalcemia and hyperphosphatemia [9]. Rare reports have described the appearance of cardiac arrhythmias (atrioventricular blocks) and syncope in these patients [9].

Short Stature
  • She also exhibited a short stature, round face and brachydactyly with shortening of the metacarpal and metatarsal bones. The serum levels of calcium, phosphorus and PTH were normal.[doi.org]
  • Further observations are necessary to define the frequency and significance of GH deficiency and the role of GH replacement therapy in pseudohypoparathyroidism- and PPHP-associated short stature.[ncbi.nlm.nih.gov]
  • The clinical presentation is practically identical for both forms - a short stature with reduced growth of metacarpal and metatarsal bones (manifesting as shorter fingers and toes, or brachydactyly), as well as obesity and a round face.[symptoma.com]
  • Short stature may be present. Obesity is less common in pseudopseudohypoparathyroidism than in pseudohypoparathyroidism. Osteoma cutis may be present.[en.wikipedia.org]
Developmental Delay
  • Measurements Cognitive impairment (CI) was defined by a history of developmental delay, learning disability and the Wechsler intelligence scale. Results CI occurred only in the five PHP‐Ia but not in the six PPHP subjects.[doi.org]
  • He showed developmental delay, short stature and short metacarpals and phalanges, which suggested Albright’s hereditary osteodystrophy. Neurologic examination revealed bilateral sixth cranial nerve palsy and bilateral papilledema.[jkna.org]
  • Additional characteristics include short stature, obesity, developmental delay, and calcification of the basal ganglia in the deep white matter of the brain.[en.wikipedia.org]
Italian
  • J Clin Endocrinol Metab 98(9):E1549–E1556 PubMed PubMedCentral CrossRef Google Scholar Copyright information Italian Society of Endocrinology (SIE) 2016 Authors and Affiliations O. Tafaj 1 H. Jüppner 1 2 Email author 1.[doi.org]
Malocclusion
  • The physical examination yielded a height of 135 cm (5 th percentile for a normal Korean girl), a round face, malocclusion of teeth and shortened left 4 th and 5 th fingers and 4 th toe ( Fig. 1 ).[doi.org]
Calcinosis Cutis
  • Early manifestation of obesity and calcinosis cutis in infantile pseudohypoparathyroidism Preamrudee Poomthavorn Department of Endocrinology and Diabetes, The Royal Children s Hospital, Melbourne, Victoria, Australia J Paediatr Child Health 42:821-3.[labome.org]
Skeletal Dysplasia
  • Although synovial manifestations of other rare skeletal dysplasias have been reported, the association of synovial osteochondromatosis and PPH has not been described. 28,29 Because synovial osteochondromatosis and PPH share in common a disorder of soft[healio.com]
Coxa Vara
Coxa Valga
Bowing of The Long Bones
  • Common musculoskeletal anomalies associated with PPH include shortening/bowing of long bones; shortening of metacarpals, metatarsals, and/or phalanges; exostoses; calcification/ossification of subcutaneous and/or periarticular soft tissues; a thickened[healio.com]
Round Face
  • She also exhibited a short stature, round face and brachydactyly with shortening of the metacarpal and metatarsal bones. The serum levels of calcium, phosphorus and PTH were normal.[doi.org]
  • She was 153 cm tall and weighed 109 kg with a round face.[endocrine-abstracts.org]
  • The clinical presentation is practically identical for both forms - a short stature with reduced growth of metacarpal and metatarsal bones (manifesting as shorter fingers and toes, or brachydactyly), as well as obesity and a round face.[symptoma.com]
  • A 62 year old man with a height of 171.5 cm, a round face, a short neck, central obesity and brachydactyly had normal ranges of serum calcium, phosphorus and PTH and a normal Ellsworth-Howard test.[e-enm.org]
Short Neck
  • A 62 year old man with a height of 171.5 cm, a round face, a short neck, central obesity and brachydactyly had normal ranges of serum calcium, phosphorus and PTH and a normal Ellsworth-Howard test.[e-enm.org]
Polyradiculoneuropathy
  • The neuropathy is thought to be similar to chronic inflammatory demyelinating polyradiculoneuropathy (CIDP); however, the relationship, if any, between PPHP and CIDP is unknown.[ncbi.nlm.nih.gov]
Limb Weakness
  • A 42 year old Greek male with pseudo-pseudohypoparathyroidism presented with difficulty in walking and with lower limb weakness.[ncbi.nlm.nih.gov]

Workup

The rare occurrence of pseudopseudohypoparathyroidism in clinical practice might present a challenge for the physicians when attempting to make the diagnosis, which is why the initial interview with the patient is crucial. In fact, the autosomal dominant pattern of inheritance mandates a positive family history, particularly from fathers who are responsible for PPHP transmission to their children, thus this piece of information may be essential for making a presumptive diagnosis [7]. Furthermore, the father should be examined as well, given the fact that they will universally present with the same signs and symptoms [8]. After a detailed physical examination that will ensure identification of skeletal-related findings, a full biochemical workup should be the next step, where serum electrolyte assessment reveals normal serum calcium and phosphate levels, whereas hormonal evaluation shows parathyroid hormone (PTH) levels within physiological limits. These findings will further point toward pseudopseudohypoparathyroidism but in order to establish a definite diagnosis, genetic testing to confirm GNAS gene mutations (both in the parents and in the affected patients) is necessary [1] [9].

Gliosis
  • Axonal loss, myelin sheath loss and gliosis were observed in the white matter with severe vascular calcification.[ncbi.nlm.nih.gov]

Treatment

  • Our patient is the first described case of PPHP associated with idiopathic GH deficiency, and the second report of long-term GH treatment in a subject with PPHP.[ncbi.nlm.nih.gov]
  • Management and treatment There are no specific treatments for the various manifestations of AHO, although subcutaneous ossifications may be surgically removed when particularly large or causing pain/discomfort.[orpha.net]
  • Please consult your own licensed physician regarding diagnosis and treatment of any medical condition! Please see also our disclaimer. This site complies with the HONcode standard for health information: verify here. Database updated 2019-02-19.[diseasesdatabase.com]
  • , misdiagnosis, research treatments, prevention, and prognosis.[search.com]

Prognosis

  • Pseudopseudohypoparathyroidism symptoms, causes, diagnosis, and treatment information for Pseudopseudohypoparathyroidism (Vitamin D resistant rickets) with alternative diagnoses, full-text book chapters, misdiagnosis, research treatments, prevention, and prognosis[search.com]
  • Prognosis Pseudo-PHP is not life threatening but quality of life can be affected in those with severe ectopic ossification. The documents contained in this web site are presented for information purposes only.[orpha.net]
  • . - administration of 3 doses of 100 000 UI Stoß vitamin D2 or D3 intramuscularly every 3 days, then a dose of 200 000 IU after 30 days oral or i.m. 37 Rickets:Evolution and prognosis Evolution is generally favorable when rickets is controlled.[slideplayer.com]

Etiology

  • Etiology The disease is caused by paternally inherited heterozygous molecular defects in the GNAS gene (20q13) encoding the alpha sub-unit of the stimulatory G protein (Gs alpha), which results in a reduction in the expression/activity of Gs alpha.[orpha.net]
  • Hypocalcemia may occur at certain stages of rickets (I and III). 46 Tetania- etiological classification II.[slideplayer.com]
  • It is suggested that the ratio of width to length of the thumbnail be included in the physical examination of children with convulsions of unknown etiology, in an effort to identify more patients with pseudo-hypoparathyroidism.[pediatrics.aappublications.org]

Epidemiology

  • Summary Epidemiology Prevalence is unknown but series of patients usually include one patient with pseudo-PHP for every two patients with PHP 1a (see this term).[orpha.net]
  • Epidemiology and Diagnosis of Hypoparathyroidism. J Clin Endocrinol Metab. 2016 Jun. 101 (6):2284-99. [Medline]. [Full Text]. Underbjerg L, Sikjaer T, Mosekilde L, Rejnmark L.[emedicine.medscape.com]
  • Journal of epidemiology /Japan Epidemiological Association. 2000; 10 (1):29–33. [ PubMed ] [ Google Scholar ] 3** Landreth H, Malow BA, Shoemaker AH. Increased Prevalence of Sleep Apnea in Children with Pseudohypoparathyroidism Type 1a.[ncbi.nlm.nih.gov]
Sex distribution
Age distribution

Pathophysiology

  • […] other conditions: Hormone resistance is not present in pseudopseudohypoparathyroidism. [5] Short stature may be present. [6] Obesity is less common in pseudopseudohypoparathyroidism than in pseudohypoparathyroidism. [7] Osteoma cutis may be present. [8] Pathophysiology[ipfs.io]
  • Pathophysiology Genetics A heterozygous mutation of the GNAS gene that encodes the G stimulatory α subunit (Gsα) of guanine nucleotide-binding protein leads to a loss of expression or function of the Gsα, which impairs the transmission of stimulatory[emedicine.medscape.com]
  • […] relaxation Normocalcemia requires PTH and normal target- organ response to PTH PTH stimulates osteoclastic bone reabsorption and distal tubular calcium reabsorption and mediates 1,25-dihydroxyvitamin D (1,25[OH]2 D) intestinal calcium absorption. 42 Pathophysiology[slideplayer.com]
  • G protein mutations in human disease L S Weinstein Molecular Pathophysiology Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 Clin Biochem 26:333-8. 1993 ..Such G protein mutations[labome.org]

Prevention

  • RightDiagnosis.com Pseudopseudohypoparathyroidism symptoms, causes, diagnosis, and treatment information for Pseudopseudohypoparathyroidism (Vitamin D resistant rickets) with alternative diagnoses, full-text book chapters, misdiagnosis, research treatments, prevention[search.com]
  • Intraoperatively, periarticular calcification or ossification of the joint capsule and collateral ligaments may prevent soft tissue balance of the knee. In our patient, a varus-valgus constrained implant was required.[healio.com]
  • […] a therapeutic effect while avoiding adverse effects that: hypercalcemia, hypercalcuria. 35 Treatment Lifestyle and nutrition It is important in the treatment and prevention of rickets triggered the disease.[slideplayer.com]
  • Genetic testing for a mutation in the GNAS1 gene can confirm diagnosis and identify subtype. [1] The goals of pharmacotherapy are to correct calcium deficiency, prevent complications, and reduce morbidity.[emedicine.medscape.com]

References

Article

  1. Simpson C, Grove E, Houston BA. Pseudopseudohypoparathyroidism. Lancet. 2015;385(9973):1123.
  2. Kottler ML, Linglart A, Carel JC. Albright hereditary osteodystrophy. Orphanet Encyclopedia 2004. https://www.orpha.net/data/patho/GB/uk-AHO.pdf
  3. Wilson LC, Hall CM. Albright's hereditary osteodystrophy and pseudohypoparathyroidism. Semin musculoskelet Radiol 2002;2013:273–83.
  4. Hamasaki H, Mukaino T, Kaneko H, et al. Journal of Endocrinology and Metabolism. 2013:3(6):150-152.
  5. Turan S, Bastepe M. GNAS spectrum of disorders. Curr Osteoporos Rep. 2015;13(3):146-158.
  6. Davies AJ, Hughes HE. Imprinting in Albright’s hereditary osteodystrophy. J Med Genet. 1993;30:101–103.
  7. Wilson LC, Oude-Luttikhuis MEM, Clayton PT, et al. Parental origin of Gsα gene mutations in Albright’s hereditary osteodystrophy. J Med Genet. 1994;31:835–839.
  8. Lemos MC, Thakker RV. GNAS Mutations in Pseudohypoparathyroidism Type 1a and Related Disorders. Hum Mutat. 2015;36(1):11-19.
  9. Rahmat N, Venables P. Sinus pauses and high-grade atrioventricular block in Albright’s hereditary osteodystrophy with pseudopseudohypoparathyroidism. BMJ Case Rep. 2013;2013:bcr2013010116.

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Last updated: 2019-07-11 20:11