Familial hypocalciuric hypercalcemia

Familial hypocalciuric hypercalcemia
Classification and external resources
OMIM	145980 145981 600740
DiseasesDB	1326

Familial hypocalciuric hypercalcemia is a condition that can cause hypercalcemia.

1 Causes
2 Differential diagnosis
3 Treatment
4 Functions of the Calcium-sensing Receptor
5 Clinical features
6 References

Causes

Types include:

Name	OMIM	Locus	Gene
HHC1	145980	3q13.3-q21	CASR
HHC2	145981	19p13.3	?
HHC3	600740	19q13^[1]	?

Most cases are associated with loss of function mutations in the CASR gene, which encodes a calcium-sensing receptor^[2], expressed in parathyroid and kidney tissue. The perceived lack of calcium levels by the parathyroid leads to constiutely high levels of parathyroid hormone, and therefore hypercalcemia.

Another form has been associated with chromosome 3q.^[3]

Differential diagnosis

This condition is indicated by the presence of hypercalcemia (elevated levels of calcium in the blood) at the same time with hypocalciuria (low levels of calcium in the urine). (Usually elevated calcium levels in the blood are correlated with elevated calcium urine levels, as a properly sensing kidney works to excrete the mineral.) A family history could reinforce the diagnosis.

Treatment

No treatment is generally required, as bone demineralisation and kidney stones are relatively uncommon in the condition. ^[4]

Functions of the Calcium-sensing Receptor

Parathyroid gland: mediates negative feedback mechanisms relating to PTH secretion (PTH secretion should decrease if there is a high blood calcium level). Abnormalities in the CASR here cause hypercalcaemia.
Kidneys: mediates negative feedback mechanisms relating to calcium reabsorption from the tubular system (reabsorption should decrease if there is a high blood calcium level). Abnormalities in the CASR here cause both hypercalcaemia and hypocalciuria.

Clinical features

Most cases: Asymptomatic (unlike primary hyperparathyroidism)
Hypercalcaemia
Hypocalciuria ( Ca excretion rate < 0.02 mmol/L).
Normal to high PTH (CaSR mutation causes the parathyroid glands to be less sensitive to serum calcium, resulting in normal to high PTH despite elevated serum calcium)
Hypermagnesaemia
Green colored urine

References

^ Lloyd SE, Pannett AA, Dixon PH, Whyte MP, Thakker RV (January 1999). "Localization of familial benign hypercalcemia, Oklahoma variant (FBHOk), to chromosome 19q13". Am. J. Hum. Genet. 64 (1): 189–95. doi:10.1086/302202. PMC 1377717. PMID 9915958. http://linkinghub.elsevier.com/retrieve/pii/S0002-9297(07)61672-3.
^ "A Practical Approach to Hypercalcemia - May 1, 2003 - American Family Physician". http://www.aafp.org/afp/20030501/1959.html. Retrieved 2009-03-29.
^ Chou YH, Brown EM, Levi T, et al. (July 1992). "The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families". Nat. Genet. 1 (4): 295–300. doi:10.1038/ng0792-295. PMID 1302026.
^ "Familial Hypouricemic Hypercalcemia". http://www.athenadiagnostics.com/content/diagnostic-ed/endocrinology/casr. Retrieved 2009-06-07.

Inborn error of metal metabolism (E83, 275)

Transition metal

Fe	high: Primary iron overload disorder: Hemochromatosis/HFE1 · Juvenile/HFE2 · HFE3 · African iron overload/HFE4 · Aceruloplasminemia · Atransferrinemia · Hemosiderosis deficiency: Iron deficiency

Cu	high: Copper toxicity · Wilson's disease deficiency: Copper deficiency · Menkes disease/Occipital horn syndrome

Zn	high: Zinc toxicity deficiency: Acrodermatitis enteropathica

Electrolyte

Na⁺ and K⁺	see Template:Water-electrolyte imbalance and acid-base imbalance

PO₄³⁻	high: Hyperphosphatemia deficiency: Hypophosphatemia · alkaline phosphatase (Hypophosphatasia)

Mg²⁺	high: Hypermagnesemia deficiency: Hypomagnesemia

Ca²⁺	high: Hypercalcaemia · Milk-alkali syndrome (Burnett's) · Calcinosis (Calciphylaxis, Calcinosis cutis) · Calcification (Metastatic calcification, Dystrophic calcification) · Familial hypocalciuric hypercalcemia deficiency: Hypocalcaemia · Osteomalacia · Pseudohypoparathyroidism (Albright's hereditary osteodystrophy) · Pseudopseudohypoparathyroidism

M: NUT

cof, enz, met

noco, nuvi, sysi/epon, met

drug(A8/11/12)

Genetic disorder, membrane: cell surface receptor deficiencies

G protein-coupled receptor
(including hormone)

Class A	TSHR (Congenital hypothyroidism 1) · LHCGR (Male-limited precocious puberty) · FSHR (XX gonadal dysgenesis) · EDNRB (ABCD syndrome, Waardenburg syndrome 4a, Hirschsprung's disease 2) · AVPR2 (Nephrogenic diabetes insipidus 1) · PTGER2 (Aspirin-induced asthma)

Class B	PTH1R (Jansen's metaphyseal chondrodysplasia)

Class C	CASR (Familial hypocalciuric hypercalcemia)

Class F	FZD4 (Familial exudative vitreoretinopathy 1)

Enzyme-linked receptor
(including
growth factor)

RTK	ROR2 (Robinow syndrome) · FGFR1 (Pfeiffer syndrome, KAL2 Kallmann syndrome) · FGFR2 (Apert syndrome, Antley-Bixler syndrome, Pfeiffer syndrome, Crouzon syndrome, Jackson-Weiss syndrome) · FGFR3 (Achondroplasia, Hypochondroplasia, Thanatophoric dysplasia, Muenke syndrome) · INSR (Donohue syndrome · Rabson–Mendenhall syndrome) · NTRK1 (Congenital insensitivity to pain with anhidrosis) · KIT (KIT Piebaldism, Gastrointestinal stromal tumor)

STPK	AMHR2 (Persistent Mullerian duct syndrome II) TGF beta receptors: Endoglin/Alk-1/SMAD4 (Hereditary hemorrhagic telangiectasia) · TGFBR1/TGFBR2 (Loeys-Dietz syndrome)

GC	GUCY2D (Leber's congenital amaurosis 1)

JAK-STAT

Type I cytokine receptor: GH (Laron syndrome) · CSF2RA (Surfactant metabolism dysfunction 4)

MPL (Congenital amegakaryocytic thrombocytopenia)

TNF receptor

TNFRSF1A (TNF receptor associated periodic syndrome) · TNFRSF13B (Selective immunoglobulin A deficiency 2) · TNFRSF5 (Hyper-IgM syndrome type 3) · TNFRSF13C (CVID4) · TNFRSF13B (CVID2) · TNFRSF6 (Autoimmune lymphoproliferative syndrome 1A)

Lipid receptor

LRP: LRP2 (Donnai-Barrow syndrome) · LRP4 (Cenani Lenz syndactylism) · LRP5 (Worth syndrome, Familial exudative vitreoretinopathy 4, Osteopetrosis 1)

LDLR (LDLR Familial hypercholesterolemia)

Other/ungrouped

Immunoglobulin superfamily: AGM3, 6

Integrin: LAD1 · Glanzmann's thrombasthenia · Junctional epidermolysis bullosa with pyloric atresia

EDAR (EDAR Hypohidrotic ectodermal dysplasia) · PTCH1 (Nevoid basal cell carcinoma syndrome) · BMPR1A (BMPR1A Juvenile polyposis syndrome) · IL2RG (X-linked severe combined immunodeficiency)

see also cell surface receptors
B structural (perx, skel, cili, mito, nucl, sclr) · DNA/RNA/protein synthesis (drep, trfc, tscr, tltn) · membrane (icha, slcr, atpa, abct, othr) · transduction (iter, csrc, itra), trfk

Congenital endocrine disease (Q89.1–Q89.2, 759.1–759.2)

Pancreas

see congenital digestive

Hypothalamic/
pituitary axes
+parathyroid

Pituitary	Congenital hypopituitarism

Thyroid	Persistent thyroglossal duct · Thyroglossal cyst Congenital hypothyroidism: Thyroid dysgenesis · Thyroid dyshormonogenesis (Pendred syndrome)

Parathyroid	Congenital absence of parathyroid

Adrenal	Absent adrenal gland

Gonads	see congenital reproductive

M: END

anat/phys/devp/horm

noco(d)/cong/tumr, sysi/epon

proc, drug (A10/H1/H2/H3/H5)