Rare Bone Diseases

OSTEOGENESIS IMPERFECTA

Disease definition

Osteogenesis imperfecta (OI) comprises a heterogeneous group of genetic disorders characterized by increased bone fragility, low bone mass, and susceptibility to bone fractures with variable severity.

Synonyms

Brittle bone disease, Glass bone disease, Lobstein disease, OI, Osteopsathyrosis

Epidemiology

Prevalence is estimated at between 1/10,000 and 1/20,000.

Clinical description

Age at diagnosis depends on the severity of the disease. Five clinically distinct types of OI have been identified. The most clinically relevant characteristic of all types of OI is bone fragility, which manifests as multiple spontaneous fractures. Osteogenesis imperfecta type II is lethal, type III is severe, types IV and V are moderate, and type I is mild (see these terms). Type I is nondeforming with normal height or mild short stature, blue sclera, and no dentinogenesis imperfecta (DI; see this term). Patients with type II present multiple rib and long bone fractures at birth, marked deformities, broad long bones, low density on skull X-rays, and dark sclera. The main signs of type III include very short stature, a triangular face, severe scoliosis, grayish sclera, and DI. Patients with type IV have moderately short stature, mild to moderate scoliosis, grayish or white sclera, and DI. Type V is characterized by mild to moderate short stature, dislocation of the radial head, mineralized interosseous membranes, hyperplastic callus, white sclera, and no DI. Other genetically different types have been observed (types VI to IX) but they are not clinically different from types II-IV.

Etiology

In 95% of cases, OI is caused by mutations in the COL1A1 and COL1A2 genes (17q21.33 and 7q21.3) encoding the alpha1 and alpha2 chains of type 1collagen. These mutations can cause all five clinical types of OI. Transmission is autosomal dominant. Autosomal recessive forms of OI are also observed and are caused by mutations in the LEPRE1, CRTAP, and PPIB genes (1p34.1, 3p22 and 15q21-q22). Autosomal recessive forms are always severe forms with severe hypotonia.

Diagnostic methods

Diagnosis is based on skeletal and extra-skeletal clinical findings. Radiological studies reveal osteoporosis and the presence of wormian-like bones. Bone densitometry confirms the low bone mass.

Differential diagnosis

Differential diagnoses include in utero diagnosis of chondrodysplasia, idiopathic juvenile osteoporosis, osteoporosis-pseudoglioma syndrome, Cole-Carpenter and Bruck syndromes, hyper or hypophosphatasia, panostotic form of polyostotic fibrous dysplasia (see these terms), non-accidental injury (multiple fractures without osteoporosis), and osteoporosis due to medication, nutritional deficiency, metabolic disease, or leukemia. The presence of several fractures should not lead to the assumption of child abuse.

Antenatal diagnosis

Antenatal diagnosis may be suspected through ultrasonography and/or confirmed through molecular analysis of amniocytes or chorionic villus cells if the causative mutation in the family has been identified.

Management and treatment

Management should be multidisciplinary involving experienced medical, orthopedic, physiotherapy and rehabilitation specialists. Bisphosphonates with potent antiresorptive properties are now considered as the standard of care for severe forms but do not constitute a cure. Prevention of vitamin D and calcium deficiency is essential throughout life. Surgical management is essential for the correction of bone and spinal deformities and the prevention of long bone fractures (centro-medullary osteosynthesis). Early physiotherapy improves autonomy by helping to evaluate any motor deficits, reducing the risk of falls and encouraging patients to take up a sporting activity.

Prognosis

Functional prognosis depends on the severity of the disease and on the quality of management. Vital prognosis depends on the severity of any respiratory complications associated with spinal deformities.

Expert reviewer(s):  Dr Véronique FORIN – Last update: March 2010

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ACHONDROPLASIA

Disease definition

Achondroplasia is the most common form of chondrodysplasia, characterized by rhizomelia, exaggerated lumbar lordosis, brachydactyly, and macrocephaly with frontal bossing and midface hypoplasia.

Epidemiology

Estimated incidence is at about 1/25,000 live births worldwide.

Clinical description

Characteristic clinical features (short limbs with rhizomelia, long and narrow trunk and macrocephaly with frontal bossing and midfacial hypoplasia with depressed nasal bridge) are visible at birth. Achievement of gross motor skills is slower than typical due to short limbs, short neck, and large head, in addition to hypotonia. Midface hypoplasia in combination with adenoid and tonsil hypertrophy can lead to obstructive sleep apnea. Chronic otitis media can lead to hearing problems. Dental crowding is common. Thoracolumbar kyphosis is very common in infancy. Most joints can be hyperextensible and hands are broad, short and trident shaped. Cord compression at the level of the foramen magnum can be encountered in infancy and early childhood causing central apnea, developmental delay, and long-track signs. Genu varum often occurs in childhood. There is also a small risk of hydrocephalus, with raised intracranial venous pressure. Lower lumbar spinal stenosis with accompanying neurological deficits, has an increased frequency in adulthood, as does cardiovascular disease. Obesity is a common issue. Adults reach a height of 131±5.6 cm (men) and 124±5.9 cm (women). Affected women must deliver by caesarian section due to small pelvis size.

Etiology

Achondroplasia is due to mutations in the fibroblast growth factor receptor 3 (FGFR3) gene, encoding a transmembrane receptor that is important in regulating linear bone growth, among other functions.

Diagnostic methods

Diagnosis is based on the presence of characteristic clinical and radiological findings. Skeletal X-rays demonstrate rhizomelia, generalized metaphyseal irregularities, narrowing of the interpediculate distance of the lower lumbar vertebrae and an abnormal pelvis with small square iliac wings and narrow sacrosciatic notch. Molecular genetic testing can confirm a diagnosis by the presence of a FGFR3 mutation.

Differential diagnosis

Differential diagnoses include hypochondroplasia, thanatophoric dwarfism (types I and II), and SADDAN (see these terms).

Antenatal diagnosis

Prenatal diagnosis can occur incidentally during routine prenatal ultrasound examination in the 3rd trimester. In high risk pregnancies, or in those where achondroplasia is suspected after an ultrasound, fetal DNA can be tested for the FGFR3 mutation to confirm diagnosis. Pre-implantation genetic diagnosis is possible in specialized laboratories.

Genetic counseling

Inheritance is autosomal dominant so genetic counseling is warranted. If one parent has achondroplasia there is a 50% chance of passing it on to offspring. In 80% of cases, it is due to a de novo mutation in children with parents of average stature. Homozygous achondroplasia is a lethal condition.

Management and treatment

Management is multidisciplinary and anticipatory care is essential. Infants may require surgical decompression of the foramen magnum, and/or shunting for hydrocephalus. Some may choose controversial limb lengthening procedures. Treatment of ear infections and serous otitis media, along with assessment of any hearing problems is needed. Speech therapy can be offered if concerns arise. Treatment of obstructed sleep apnea may include adenotonsillectomy, weight loss, and/or continuous positive airway pressure. Surgical correction can re-align bowing of legs. Adult patients may require a lumbar laminectomy to treat spinal stenosis. Weight gain should be monitored in childhood to avoid later complications. Activities which lead to a risk of injury to the craniocervical junction should be avoided. Social and psychological support should be offered.

Prognosis

There is only a slight decrease in life expectancy compared to the general population, potentially due to cardiovascular disease.

Expert reviewer

 Dr Michael BOBER – Angela DUKER – Last update: April 2013

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HYPOPHOSPHATASIA

Disease definition

Hypophosphatasia (HPP) is a rare heritable metabolic disorder characterized by defective mineralization of bone and/or teeth in the presence of reduced activity of unfractionated serum alkaline phosphatase (ALP). The clinical spectrum is extremely wide, from stillbirth at one end to fractures of the lower extremities in adulthood, at the other, or even no bone manifestations (odontohypophosphatasia).

Epidemiology

Exact prevalence and incidence data for hypophosphatasia are not available. The prevalence ofsevere forms of the disease has been estimated to be 1/300,000 births in Europe.

Clinical description

Six different clinical forms of HPP have been described. Prenatal benign hypophosphatasia involves prenatal skeletal manifestations that slowly resolve to become the milder childhood or adult form. Perinatal lethal hypophosphatasia involves significant hypomineralization and leads to hypercalcemia and respiratory insufficiency. Infantile hypophosphatasia is characterized by rickets developing between birth and six months of age. Childhood-onset hypophosphatasia ranges from low bone mineral density with unexplained fractures to rickets. Adult hypophosphatasia involves early loss of adult dentition and stress fractures of the lower extremities in middle age. Lastly, odontohypophosphatasia includes premature exfoliation of primary teeth and/or severe dental caries. Rare cases of infantile hypophosphatasia that have normal serum alkaline phosphatase activity are known as ”pseudohypophosphatasia”.

Etiology

More than 250 different mutations in the ALPL gene (1p36.12) are known to cause hypophosphatasia. The gene encodes alkaline phosphatase, tissue-nonspecific isozyme (TNSALP) involved in skeletal mineralization.

Diagnostic methods

The diagnosis is based on laboratory testing and molecular genetic testing of the ALPL gene to detect causative mutations. Serum alkaline phosphatase (AP) activity is markedly reduced while urinary phosphoethanolamine (PEA) is increased but these abnormalities are not pathognomonic. Ultrasound is used in prenatal and perinatal forms. Clinical examinations and radiographs help to establish the diagnosis in infantile, childhood and adult forms.

Differential diagnosis

The differential diagnosis includes osteogenesis imperfecta and campomelic dysplasia in early diagnosis, and hypophosphatemic rickets and achondrogenesis in later diagnosis (see these terms).

Antenatal diagnosis

Prenatal diagnosis can be performed through mutation analysis following chorionic villus sampling.

Genetic counseling

Perinatal and severe infantile HPP are inherited as autosomal recessive traits. Prenatal benign, moderate infantile, childhood HPP, adult HPP and odontohypophosphatasia can be inherited in an autosomal recessive or autosomal dominant manner, depending on the specific effect the gene mutation has on TNSALP activity. The less severe the disease, the more likely it is dominantly inherited. The range of inheritance patterns partially explains the clinical heterogeneity. In autosomal recessive hypophosphatasia, rare de novo mutations have been reported. In autosomal dominant hypophosphatasia, affected patients may have an affected parent but penetrance appears to be low and de novo mutations have not been reported. HPP displays highly variable expressivity. Genetic counseling is complicated by these factors but should be offered to affected families.

Management and treatment

Supportive symptomatic treatment in childhood and adult forms includes non-steroidal anti-inflammatory drugs (children), teriparatide (adults) and orthopedic management. Dental monitoring and care are essential. Enzyme replacement therapy also plays a role. Bisphosphonates are generally contraindicated in hypophosphatasia.

Prognosis

The perinatal form is almost always fatal within days or weeks. Respiratory complications lead to high mortality rates in the infantile form. Life expectancy is not thought to be affected in the adult form or in odontohypophosphatasia.

Expert reviewer

Pr Etienne MORNET – Last update: April 2015

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MULTIPLE OSTEOCHONDROMAS

Disease definition

Multiple osteochondromas (MO) is characterised by development of two or more cartilage capped bony outgrowths (osteochondromas) of the long bones.

Synonym

Bessel-Hagen disease, Multiple cartilaginous exostoses

Epidemiology

The prevalence is estimated at 1:50,000, and seems to be higher in males (male-to-female ratio 1.5:1).

Clinical description

Osteochondromas develop and increase in size in the first decade of life, ceasing to grow when the growth plates close at puberty. They are pedunculated or sessile (broad base) and can vary widely in size. The number of osteochondromas may vary significantly within and between families, the mean number of locations is 15-18. The majority are asymptomatic and located in bones that develop from cartilage, especially the long bones of the extremities, predominantly around the knee. The facial bones are not affected. Osteochondromas may cause pain, functional problems and deformities (especially of the forearm), which may provide reason for surgical removal. The most important complication is malignant transformation of osteochondroma towards secondary peripheral chondrosarcoma, which is estimated to occur in 0.5-5% of cases.

Etiology

Germline mutations in the tumour suppressor genes, EXT1 or EXT2, are found in almost 90% of MO patients. The EXT genes encode glycosyltransferases, catalyzing heparan sulphate polymerization.

Diagnostic methods

The diagnosis is based on radiological and clinical documentation, supplemented with, if available, histological evaluation of the osteochondromas.

Differential diagnosis

MO should be distinguished from metachondromatosis, dysplasia epiphysealis hemimelica and Ollier disease (see these terms).

Antenatal diagnosis

If the exact mutation is known antenatal diagnosis is technically possible.

Genetic counseling

MO is an autosomal dominant disorder and is genetically heterogeneous.

Management and treatment

Management includes removal of osteochondromas when they are the cause of complaints. Removed osteochondromas should be examined for malignant transformation towards secondary peripheral chondrosarcoma. Patients should be well instructed and regular follow-up for early detection of malignancy seems justified. For secondary peripheral chondrosarcoma, en-bloc resection of the lesion and its pseudocapsule with tumour-free margins should be performed, preferably in a bone tumour referral centre.

Prognosis

Osteochondromas are benign lesions and do not affect life expectancy.

Expert reviewer

 Pr J.V.M.G. [Judith] BOVÉE – Last update: February 2008

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FIBROUS DYSPLASIA/MCCUNE-ALBRIGHT SYNDROME 

Disease definition

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS; OMIM#174800)

Epidemiology

The exact prevalence of fibrous dysplasia is unknown, but it is less than 1:2000.

Clinical description

FD/MAS is a rare disorder characterized by skeletal lesions, skin hyperpigmentation, and hyper-functioning endocrinopathies

Etiology

It arises from post-zygotic gain-of-function mutations in the GNAS gene, which encodes the α-subunit of the Gs signalling protein. These mutations disrupt the intrinsic GTPase activity of Gsα, leading to persistent stimulation of adenylyl cyclase and dysregulated production of cyclic AMP and downstream signalling. The resulting disease is mosaic with a broad clinical spectrum, ranging from a trivial incidentally discovered radiographic finding to severe and disabling disease.

Diagnostic methods

A diagnosis of the subtypes of FD/MAS can only be made after a thorough evaluation of a) the extent of skeletal disease: monostotic/polyostotic and b) the presence of extra-skeletal manifestations. Monostotic fibrous dysplasia is defined as the presence of fibrous dysplasia in one skeletal site only. Polyostotic fibrous dysplasia is defined as the presence of fibrous dysplasia in more than one skeletal site without extra-skeletal manifestations. McCune-Albright syndrome is defined as the combination of FD and one or more extra-skeletal feature, OR the presence of two or more extra skeletal features. Not requiring FD for the diagnosis of MAS reflects better understanding of the molecular pathogenesis of the disorder. Mazabraud Syndrome is the combination of FD with intramuscular myxoma(s). The myxoma is defined as an extra-skeletal manifestation of FD/MAS and may occur in association with any type of the disease (monostotic, polyostotic or MAS).  Other extra-skeletal features include:

  1. Café-au-lait skin macules with characteristic features of jagged, irregular borders (Coast of Maine) and a distribution showing the so-called “respect of” the midline of the body
  2. Gonadotropin-independent sex steroid production resulting in precocious puberty, recurrent ovarian cysts in girls and women or autonomous testosterone production in boys and men. This includes testicular lesions consistent with FD/MAS with or without associated gonadotropin-independent precocious puberty.
  3. Thyroid lesions consistent with FD/MAS with or without non-autoimmune hyperthyroidism
  4. Growth hormone excess
  5. Neonatal hypercortisolism

Of note, FGF-23-associated hypophophataemia is not considered a feature of MAS but rather a marker of the severity of skeletal FD.

Differential diagnosis

.

Antenatal diagnosis

Not applicable.

Genetic counseling

While a genetic disease, the mutation occurs after fertilization and so can not be inherited.

Management and treatment

Management consists of general measures (Provision of information about the disease, Lifestyle advice, Exercise and rehabilitation) and specific measures including management of FGF-23 induced renal phosphate wasting, Scoliosis, bone pain, Mazabraud syndrome, endocrinopathies of the ovary, testes, thyroid, pituitary and adrenals, haematological manifestations, gastrointestinal manifestations and increased risk of malignancy. Surgical management includes orthopaedic, spinal, craniofacial, maxillofacial and dental aspects.

Prognosis

Very variable depending on severity and response to drug and surgical treatment.

For patients

DO: Seek a specialist who has experience in treating people with Fibrous dysplasia/McCune-Albright syndrome. You are not alone as a person with FD/MAS or a parent or carer. Do connect with patients groups in Fibrous dysplasia/McCune-Albright syndrome – start at the Fibrous Dysplasia Foundation https://fibrousdysplasia.org/resources-for-patients/related-organizations/ or search Facebook or social media.

DON’T: Lose hope, there is usually something that can be done to help you. Don’t be put off by doctors who say there is nothing that can be done. Ask to see a specialist and use your patient groups.

Expert reviewer

MK Javaid 

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Javaid MK et al., Best practice management guidelines for fibrous dysplasia/McCune-Albright syndrome: a consensus statement from the FD/MAS international consortium. Orphanet J Rare Dis. 2019 Jun 13;14(1):139. doi: 10.1186/s13023-019-1102-9.

PSEUDOHYPOPARATHYROIDISM, ALBRIGHT’S HEREDITARY OSTEODYSTROPHY & RELATED DISORDERS

Disease definition

The term PHP (Online Mendelian Inheritance in Man, OMIM) #103580 for PHP type 1A (PHP1A), #603233 for PHP type IB (PHP1B) and #612462 for PHP type 1C (PHP1C)) describes disorders that share common biochemical features of hypoparathyroidism (that is, hypocalcaemia and hyperphosphataemia) that are the result of resistance of target tissues to the biological actions of parathyroid hormone (PTH). Patients with PHP1A and PHP1C are also characterized by the variable expression of a collection of physical features, termed Albright hereditary osteodystrophy (AHO). Furthermore, based on the number of AHO features and the presence and extent of ectopic ossifications, patients might be classified as having pseudopseudohypoparathyroidism (PPHP; OMIM #612463), progressive osseous heteroplasia (POH; OMIM #166350) or osteoma cutis. Acrodysostosis (OMIM #101800) refers to a group of chondrodysplasias that resemble PHP in some patients, owing to the presence of brachydactyly and often resistance to different hormones, but differ from PHP owing to more extensive facial dysmorphism, nasal hypoplasia and often developmental delay.

Note: recently, a new nomenclature and classification of these heterogeneous but overlapping diseases has been proposed, referring to these disorders as inactivating PTH/PTHrP Signalling Disorders (iPPSDs): Thiele S et al. From Pseudohypoparathyroidism to inactivating PTH/PTHrP Signalling Disorder (iPPSD), a novel classification proposed by the European EuroPHP network. Eur J Endocrinol. 2016 Dec; 175 (6): P1-P17. PubMed PMID: 27401862.

 

Epidemiology

The exact prevalence of PHP is unknown. Studies published in 2000 and 2016 estimated the prevalence to be 0.34 in 100,000 in Japan and 1.1 in 100,000 in Denmark. The prevalence of POH has never been estimated. However, it seems to be extremely rare, as <60 cases have been reported worldwide up to December 2016. The prevalence of Acrodysostosis is unknown as clinical, biochemical and radiological features overlap with those of PHP1A and PPHP.

Clinical description

All forms of PHP can present in infancy, especially if significant hypocalcemia occurs. Symptoms related to low levels of calcium can include: paresthesias, numbness, seizures and tetany (including muscle twitches and hand and foot spasms).Some forms of PHP may remain unnoticed if patients do not have hypocalcemia and/or characteristic physical features, which include short stature, rounded face, short neck, brachydactyly, ectopic ossifications and other poorly defined abnormalities, collectively termed Albright hereditary osteodystrophy (AHO). In some patients, the physical features of AHO might be present in the absence of hormone resistance. Patients with extensive and deep ectopic ossifications are classified as progressive osseous heteroplasia (POH). Other features have been attributed to these disorders since their identification, such as intrauterine growth failure, early-onset obesity (that is, development in the first few months of life and full expression before the end of infancy), hypothyroidism due to resistance to thyroid stimulating hormone (TSH), hypogonadism, growth hormone (GH) deficiency and cognitive impairment, including developmental delay and loss of intellectual function. In acrodysostosis brachydactyly is usually more marked and is associated with more extensive facial dysmorphism, nasal hypoplasia and often developmental delay, in addition to frequent resistance to PTH and TSH.

Etiology

All patients with PHP and PHP-related disorders in whom a molecular diagnosis is confirmed have genetic or epigenetic alterations in genes encoding for proteins involved in the PTH/PTHrP signaling pathway. PHP1A, PPHP and POH are due to genetic defects in the gene coding the alpha sub-unit of the stimulatory G protein (GNAS, 20q13.2-q13.3). The pattern of inheritance is consistent with a tissue-specific paternal imprinting of the gene causing the disease. Patients with PHP1B show an alteration of the methylation pattern of the GNAS locus. Those with the autosomal dominant form of PHP1B often display a recurrent 3-kb deletion in the STX16 gene (20q13.32). Patients with Acrodysostosis display mutations within either the PRKAR1A or the PDE4D genes.

Diagnostic methods

The diagnosis is based on the presence of characteristic clinical and endocrinological findings. 
When the clinical pattern is highly suggestive of alteration of a specific gene, Sanger sequencing of that gene is proposed. When the clinical presentation is not suggestive of a specific gene, a targeted gene panel encompassing genes that encode proteins involved in the PTH–parathyroid hormone-related protein (PTHrP) signalling pathway might be performed. The parental origin of the variant could have important clinical implications; thus, parental testing is indicated when a genetic alteration is detected. Methylation analysis of the GNAS locus by MS-MLPA is indicated in those cases with isolated hormone resistance and/or mild bone phenotype.

Differential diagnosis

Differential diagnoses of PHP and related disorders based on the main clinical presentation

Leading symptom

Differential diagnosis

Associated signs or comments

Hypocalcaemia with elevated PTH

Vitamin D deficiency or resistance

– Improvement upon vitamin D therapy
– Rickets, alopecia

Rickets

– Enlargement of the metaphyses 
– Leg bowing 
– Elevated ALP

Hypoparathyroidism due to a mutation in the PTH gene

Use different assays to confirm the elevated PTH

Brachydactyly

Tricho-rhino-phalangeal syndrome due to TRPS1 mutations

– Dysmorphism: slowly growing and sparse scalp hair, laterally sparse eyebrows, bulbous tip of the nose, long flat philtrum, thin upper vermillion border and protruding ears
– Hip dysplasia, small feet and a short hallux, exostosis and ivory epiphyses

Isolated brachydactyly type E due to HOXD13 mutations

– Syndactyly, long distal phalanges and shortening of the distal phalanx of the thumb
– Hypoplasia/aplasia, lateral phalangeal duplication and/or clinodactyly

Brachydactyly mental retardation syndrome due to 2q37 microdeletions

– Obesity, short stature
– Brachydactyly
– Psychomotor and cognitive alterations

Turner Syndrome due to partial or complete loss of one X chromosome

– Short stature, low birth weight, gonadal failure, and variable neurocognitive defects
– Brachydactyly and Madelung deformity

Brachydactyly type E with short stature due to PTHLH mutations 

– Short stature of variable severity, impaired breast development
– Oligodontia, delayed tooth eruption, dental malposition
– Pseudoepiphyses, brachydactyly

Ossifications- Subcutaneous

 

Acne vulgaris

 

Cutaneous tumors such as primarily pilomatricomas, chondroid syringomas, basal cell carcinomas, pilar cysts and nevi

Secondary or traumatic osteoma cutis and miliary ostoma

 

Inflammatory conditions such as scars, chronic venous stasis, morphea, scleroderma, dermatomyositis, and myositis ossificans progressiva

 

Ossifications- Progressive

Fibrodysplasia Ossificans Progressiva

due to a recurrent activating missense mutation of ACVR1

– Progressive ossification of skeletal muscle, tendons, fascia and ligaments
– Upper back and neck are the first parts of the skeleton to be affected; trauma alters the natural progression of the disease 
– Congenital malformation of the great toes

Tumoral calcinosis

Due to FGF23 or GALNT3 mutations

– Deposition of calcium within the skin and/or muscles
– Hyperphosphataemia

Early-onset obesity

Beckwith-Wiedemann syndrome

– Hemihypertrophy
– Macroglossia

Genetic, cytogenetic or syndromic anomalies associated with early onset obesity, including:

 – Prader-Willi syndrome

 – Monogenic obesity (mutations in POMC, MC4R, leptin, leptin receptor)

 

Early onset hypothyroidism

 

Congenital hypothyroidism of any cause

– Small thyroid in size, in place 
– TSH moderately elevated

TSH resistance due to mutations in the TSH receptor

 

Hypertension

Autosomal dominant hypertension and brachydactyly type E syndrome

Short stature

Antenatal diagnosis

There are very few cases with antenatal diagnosis of PHP or PPHP, as their clinical manifestations are usually not specific within this period. The bone dysplasia observed in patients with acrodysostosis might display a prenatal onset, mostly when caused by PRKAR1A mutations.

Genetic counseling

PHP can be sporadic or inherited autosomal dominantly with parental imprinting. In inherited cases, genetic counseling is possible.

Management and treatment

A multidisciplinary follow-up and early, specific interventions are necessary for efficient therapeutic management of these patients.
Management consists of general measures (lifestyle advice for obesity, exercise and rehabilitation) and specific measures aimed to correct hypocalcemia, growth retardation and other endocrine deficiencies. Surgical management may include orthopaedic, spinal and dental aspects.

Prognosis

Very variable depending on age at onset, severity and presence or absence of endocrine abnormalities..

For patients

DO: Seek a specialist who has experience in treating people with rare disease of mineral metabolism. Do connect with patients groups on Facebook or social media.

Expert reviewer

G Mantovani

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Mantovani G et al., Diagnosis and management of Pseudohypoprathyroidism and related disorders: first international consensus statement. Nat Rev Endocrinol. 2018 14(8):476-500. doi: 10.1038/s41574-018-0042-0. Review. PubMed PMID: 29959430