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Autosomal recessive hypophosphatemic bone disease(HHRH)

MedGen UID:
501133
Concept ID:
C1853271
Disease or Syndrome
Synonyms: Hereditary Hypophosphatemic Rickets with Hypercalciuria; HHRH; HYPERCALCIURIC RICKETS; Hypophosphatemic rickets with hypercalciuria
SNOMED CT: Hereditary hypophosphatemic rickets with hypercalciuria (726081005); HHRH - hereditary hypophosphatemic rickets with hypercalciuria (726081005); Autosomal recessive hypophosphatemic bone disease (237891005)
Modes of inheritance:
Autosomal recessive inheritance
MedGen UID:
141025
Concept ID:
C0441748
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in individuals with two pathogenic alleles, either homozygotes (two copies of the same mutant allele) or compound heterozygotes (whereby each copy of a gene has a distinct mutant allele).
Autosomal dominant inheritance
MedGen UID:
141047
Concept ID:
C0443147
Intellectual Product
Source: Orphanet
A mode of inheritance that is observed for traits related to a gene encoded on one of the autosomes (i.e., the human chromosomes 1-22) in which a trait manifests in heterozygotes. In the context of medical genetics, an autosomal dominant disorder is caused when a single copy of the mutant allele is present. Males and females are affected equally, and can both transmit the disorder with a risk of 50% for each child of inheriting the mutant allele.
 
Gene (location): SLC34A3 (9q34.3)
 
Monarch Initiative: MONDO:0009431
OMIM®: 241530
Orphanet: ORPHA157215

Definition

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare autosomal recessive disorder characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histologic evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption (summary by Bergwitz et al., 2006). [from OMIM]

Additional description

From MedlinePlus Genetics
Hereditary hypophosphatemic rickets is a disorder related to low levels of phosphate in the blood (hypophosphatemia). Phosphate is a mineral that is essential for the normal formation of bones and teeth.

In most cases, the signs and symptoms of hereditary hypophosphatemic rickets begin in early childhood. The features of the disorder vary widely, even among affected members of the same family. Mildly affected individuals may have hypophosphatemia without other signs and symptoms. More severely affected children experience slow growth and are shorter than their peers. They develop bone abnormalities that can interfere with movement and cause bone pain. The most noticeable of these abnormalities are bowed legs or knock knees. These abnormalities become apparent with weight-bearing activities such as walking. If untreated, they tend to worsen with time.

Other signs and symptoms of hereditary hypophosphatemic rickets can include premature fusion of the skull bones (craniosynostosis) and dental abnormalities. The disorder may also cause abnormal bone growth where ligaments and tendons attach to joints (enthesopathy). In adults, hypophosphatemia is characterized by a softening of the bones known as osteomalacia.

Another rare type of the disorder is known as hereditary hypophosphatemic rickets with hypercalciuria (HHRH). In addition to hypophosphatemia, this condition is characterized by the excretion of high levels of calcium in the urine (hypercalciuria).

Researchers have described several forms of hereditary hypophosphatemic rickets, which are distinguished by their pattern of inheritance and genetic cause. The most common form of the disorder is known as X-linked hypophosphatemic rickets (XLH). It has an X-linked dominant pattern of inheritance. X-linked recessive, autosomal dominant, and autosomal recessive forms of the disorder are much rarer.  https://medlineplus.gov/genetics/condition/hereditary-hypophosphatemic-rickets

Clinical features

From HPO
Bone pain
MedGen UID:
57489
Concept ID:
C0151825
Sign or Symptom
An unpleasant sensation characterized by physical discomfort (such as pricking, throbbing, or aching) localized to bone.
Hypercalciuria
MedGen UID:
43775
Concept ID:
C0020438
Finding
Abnormally high level of calcium in the urine.
Renal tubular dysfunction
MedGen UID:
57484
Concept ID:
C0151747
Disease or Syndrome
Abnormal function of the renal tubule. The basic functional unit of the kidney, the nephron, consists of a renal corpuscle attached to a renal tubule, with roughly 0.8 to 1.5 nephrons per adult kidney. The functions of the renal tubule include reabsorption of water, electrolytes, glucose, and amino acids and secretion of substances such as uric acid.
Renal phosphate wasting
MedGen UID:
335116
Concept ID:
C1845169
Finding
High urine phosphate in the presence of hypophosphatemia.
Calcium nephrolithiasis
MedGen UID:
344578
Concept ID:
C1855801
Finding
The presence of calcium-containing calculi (stones) in the kidneys.
Tibial bowing
MedGen UID:
332360
Concept ID:
C1837081
Finding
A bending or abnormal curvature of the tibia.
Enlargement of the wrists
MedGen UID:
325479
Concept ID:
C1838663
Finding
Enlargement of the ankles
MedGen UID:
333151
Concept ID:
C1838664
Finding
Fibular bowing
MedGen UID:
869374
Concept ID:
C4023801
Anatomical Abnormality
A bending or abnormal curvature of the fibula.
Growth delay
MedGen UID:
99124
Concept ID:
C0456070
Pathologic Function
A deficiency or slowing down of growth pre- and postnatally.
Failure to thrive
MedGen UID:
746019
Concept ID:
C2315100
Disease or Syndrome
Failure to thrive (FTT) refers to a child whose physical growth is substantially below the norm.
Gait disturbance
MedGen UID:
107895
Concept ID:
C0575081
Finding
The term gait disturbance can refer to any disruption of the ability to walk.
Recurrent fractures
MedGen UID:
42094
Concept ID:
C0016655
Injury or Poisoning
The repeated occurrence of bone fractures (implying an abnormally increased tendency for fracture).
Hypotonia
MedGen UID:
10133
Concept ID:
C0026827
Finding
Hypotonia is an abnormally low muscle tone (the amount of tension or resistance to movement in a muscle). Even when relaxed, muscles have a continuous and passive partial contraction which provides some resistance to passive stretching. Hypotonia thus manifests as diminished resistance to passive stretching. Hypotonia is not the same as muscle weakness, although the two conditions can co-exist.
Rickets
MedGen UID:
48470
Concept ID:
C0035579
Disease or Syndrome
Rickets is divided into two major categories including calcipenic and phosphopenic. Hypophosphatemia is described as a common manifestation of both categories. Hypophosphatemic rickets is the most common type of rickets that is characterized by low levels of serum phosphate, resistance to ultraviolet radiation or vitamin D intake. There are several issues involved in hypophosphatemic rickets such as calcium, vitamin D, phosphorus deficiencies. Moreover, other disorder can be associated with its occurrence such as absorption defects due to pancreatic, intestinal, gastric, and renal disorders and hepatobiliary disease. Symptoms are usually seen in childhood and can be varied in severity. Severe forms may be linked to bowing of the legs, poor bone growth, and short stature as well as joint and bone pain. Hypophosphatemic rickets are associated with renal excretion of phosphate, hypophosphatemia, and mineral defects in bones. The familial type of the disease is the most common type of rickets.
Muscle weakness
MedGen UID:
57735
Concept ID:
C0151786
Finding
Reduced strength of muscles.
Frontal bossing
MedGen UID:
67453
Concept ID:
C0221354
Congenital Abnormality
Bilateral bulging of the lateral frontal bone prominences with relative sparing of the midline.
Difficulty standing
MedGen UID:
69136
Concept ID:
C0241237
Sign or Symptom
Hypophosphatemic rickets
MedGen UID:
309957
Concept ID:
C1704375
Disease or Syndrome
Rickets due to low serum phosphate concentrations, the cause of which can be nutritional or genetic. This condition is characterized by normal parathyroid hormone concentrations, usually caused by renal phosphate wasting occurring in isolation or as part of a renal tubular disorder, and characterized by resistance to treatment with ultraviolet radiation or vitamin D.
Sparse bone trabeculae
MedGen UID:
371538
Concept ID:
C1833324
Finding
Thin bony cortex
MedGen UID:
318844
Concept ID:
C1833325
Finding
Abnormal thinning of the cortical region of bones.
Bulging epiphyses
MedGen UID:
371540
Concept ID:
C1833329
Finding
A morphological abnormality of epiphyses whereby they are abnormally outwardly curving (protuberant).
Flat occiput
MedGen UID:
332439
Concept ID:
C1837402
Finding
Reduced convexity of the occiput (posterior part of skull).
Deformed rib cage
MedGen UID:
374021
Concept ID:
C1838659
Anatomical Abnormality
Malformation of the rib cage.
Metaphyseal irregularity
MedGen UID:
325478
Concept ID:
C1838662
Finding
Irregularity of the normally smooth surface of the metaphyses.
Bulging of the costochondral junction
MedGen UID:
338492
Concept ID:
C1848538
Finding
Abnormal outward curving (protuberance) of the junction of ribs and costal cartilage.
Widely patent fontanelles and sutures
MedGen UID:
336570
Concept ID:
C1849300
Finding
An abnormally increased width of the cranial fontanelles and sutures.
Enlargement of the costochondral junction
MedGen UID:
346535
Concept ID:
C1857180
Finding
Abnormally increased size of the costochondral junctions, which are located between the distal part of the ribs and the costal cartilages, which are bars of hyaline cartilage that connect the ribs to the sternum.
Femoral bowing
MedGen UID:
347888
Concept ID:
C1859461
Finding
Bowing (abnormal curvature) of the femur.
Delayed epiphyseal ossification
MedGen UID:
351324
Concept ID:
C1865200
Finding
Bowing of the legs
MedGen UID:
1807399
Concept ID:
C5574706
Finding
A bending or abnormal curvature affecting a long bone of the leg.
Hypophosphatemia
MedGen UID:
39327
Concept ID:
C0085682
Disease or Syndrome
An abnormally decreased phosphate concentration in the blood.
Decreased circulating parathyroid hormone level
MedGen UID:
1630961
Concept ID:
C0729198
Finding
An abnormally decreased concentration of parathyroid hormone.
Elevated circulating alkaline phosphatase concentration
MedGen UID:
727252
Concept ID:
C1314665
Finding
Abnormally increased serum levels of alkaline phosphatase activity.
Abnormal circulating calcium concentration
MedGen UID:
868059
Concept ID:
C4022450
Finding
Any deviation from the normal concentration of calcium in the blood circulation.
High serum calcitriol
MedGen UID:
1619023
Concept ID:
C4531136
Finding
An increased concentration of calcitriol in the blood. Calcitriol is also known as 1,25-dihydroxycholecalciferol or 1,25-dihydroxyvitamin D3.
High serum calcifediol
MedGen UID:
1616110
Concept ID:
C4531137
Finding
An increased concentration of calcifediol in the blood. Calcifediol is also known as 25-hydroxycholecalciferol or 25-Hydroxyvitamin D3.

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVAutosomal recessive hypophosphatemic bone disease

Recent clinical studies

Therapy

Scriver CR, Reade TM, DeLuca HF, Hamstra AJ
N Engl J Med 1978 Nov 2;299(18):976-9. doi: 10.1056/NEJM197811022991803. PMID: 308618

Clinical prediction guides

Scriver CR, Reade TM, DeLuca HF, Hamstra AJ
N Engl J Med 1978 Nov 2;299(18):976-9. doi: 10.1056/NEJM197811022991803. PMID: 308618

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