- Alport Syndrome (Hereditary nephritis).

Alport Syndrome (Hereditary nephritis)

AS, or hereditary nephritis, is a genetically heterogeneous disease caused by mutations in the genes coding for type IV collagen, a major component of basement membranes which is present in kidney, ear, and ocular lens.

GENETICS

• The most common form of hereditary nephritis.
• Approximately 85% of patients have X-linked inheritance caused by a mutation in the COL4A5 gene encoding the α5 chain of type IV collagen.
• Autosomal recessive forms of AS (10%)are caused by mutations in the COL4A3 and COL4A4 genes on chromosome 2 encoding the α3 and α4 chains, respectively, of type IV collagen.
• An autosomal dominant form of AS linked to the COL4A3-COL4A4 gene locus occurs in 5% of cases.

PATHOLOGY
- Light microscopy:

• Kidney biopsy specimens during the 1st decade of life show few changes
• Later, the glomeruli may develop mesangial proliferation and capillary wall thickening, leading to progressive glomerular sclerosis. Tubular atrophy, interstitial inflammation and fibrosis, and lipid-containing tubular or interstitial cells, called foam cells, develop as the disease progresses.

- The Syndrome of Pyogenic Arthritis with Pyoderma Gangrenosum and Acne.

The Syndrome of Pyogenic Arthritis with Pyoderma Gangrenosum and Acne

PAPA syndrome is a rare autosomal dominant disorder caused by mutations in PSTPIP1, a gene located on chromosome 15 that encodes the cytoskeletal proline serine threonine phosphatase-interacting (PSTPIP) protein. 

Clinical manifestations:

• Recurrent episodes of sterile, pyogenic arthritis that leads to erosions and joint destruction, and appears to develop spontaneously or after minor trauma. The onset of arthritis is often in early childhood.
• Cutaneous manifestations tend to develop in adolescence, at which time patients are prone to developing severe cystic acne.
• PAPA patients commonly develop ulcerating pyoderma gangrenosum lesions  and some develop pathergy reactions

- Cryopyrin-associated periodic syndromes.

Cryopyrin-associated periodic syndromes (CAPSs)

CAPS includes a spectrum of conditions ranging from mild to severe, and includes three syndromes:

• FCAS.
•  MWS.
• CINCA/NOMID.

INCIDENCE/AETIOLOGY:

CAPS is extremely rare, with an incidence of probably <1 in 500,000.

CAPS is due to mutations in NLRP3/CIAS1 on chromosome 1q44, that encodes the key component of IL-1 activation complex: the inflammasome.

A dominant inheritance occurs in about 75% of patients with FCAS and MWS, whereas CINCA is usually due to de novo mutations 

.

CLINICAL PRESENTATION:-

Onset is in early infancy, often from birth; there is no sex bias.

Children present with a characteristic appearance of flattened nasal bridge and bossing of the skull.

•  FCAS: attacks of fever generally begin 1-3 hr after generalized cold exposure, urticarial rash, arthralgia and conjunctivitis, episodes are self-limited and generally resolve within 24 hr.
• MWS: daily attacks (afternoon/evenings), Acute symptoms include fever, urticarial rash, arthralgia and myalgia, conjunctivitis, headache and fatigue.Rash can be persistent.Deafness occurs later and is often missed in the early stages.
• CINCA/NOMID: continuous inflammation with additional severe chronic aseptic meningitis, raised intracranial pressure, uveitis, deafness and arthropathy.

- Hyperimmunoglobulinemia D with periodic fever syndrome.

Hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)

/ Mevalonate kinase deficiency (MKD)

INCIDENCE/AETIOLOGY

MKD/HIDS is extremely rare. Most patients are North European, many in Holland (it was called ‘Dutch fever’), but can occur in other ethnicities.

The disease is caused by mutations of MVK, a gene located on the long arm of chromosome 12 that encodes mevalonate kinase (MK).

CLINICAL PRESENTATION

• Onset of MKD/HIDS within the 1st 6 mo of life.
• Children experience irregular attacks that may be precipitated by vaccination, minor trauma, surgery or stress.
• Attacks last 4–7 days.
•  Fever, unilateral or bilateral cervical lymphadenopathy, abdominal pain with vomiting and diarrhea, headache, arthralgia, large joint arthritis, erythematous macules and papules and aphthous ulcers are common.
• A history of high fevers or a full attack with vaccination is often obtained

- Cystinosis (liginac Syndrome).

Cystinosis (liginac Syndrome)

A/E:  defect in the metabolism of cysteine that results in accumulation of cystine crystals in most of the major organs of the body, notably the kidney, liver, eye, and brain.

Incidence:

-       It occurs at an incidence of 1 : 100,000 to 1 : 200,000.

-       Is the most common cause of Fanconi syndrome in children.

-       In certain populations, such as French Canadians, the incidence is much higher.

clinical patterns:

1.    Infantile or nephropathic cystinosis: the most severe form present in the 1st 2 yr of life with severe tubular dysfunction and growth failure. If the disease is not treated, the children develop end-stage renal disease by the end of their 1^st decade.

2.    A milder form of the disease manifests in adolescents and is characterized by less-severe tubular abnormalities and a slower progression to renal failure.

3.    A benign adult form with no renal involvement also exists.

-  Patients with nephropathic cystinosis present with clinical manifestations reflecting their pronounced tubular dysfunction and Fanconi syndrome…?

-  Patients are typically fair skinned and blond because of diminished pigmentation.

-  Ocular presentations include photophobia, retinopathy, and impaired visual acuity.

-  Patients also can develop hypothyroidism, HSM, and delayed sexual maturation.

-  With progressive tubulointerstitial fibrosis, renal insufficiency is invariant.

- Lowe Syndrome.

Lowe Syndrome

Lowe syndrome (oculocerebrorenal syndrome of Lowe) is a rare X-linked disorder characterized by:

-       congenital cataracts , glaucoma and blindness often develop.

-       mental retardation, hypotonia and hyporeflexia,

-       The renal abnormalities are tubular and include: hypophosphatemic rickets with ↓ serum phosphorus levels, low to normal serum calcium Levels,↑ serum alkaline phosphatase levels,pRTA, and aminoaciduria.

-  Significant proteinuria is common.

-  The disease is caused by mutations in the OCRL1 gene, which codes for a Golgi aparatus phosphatase.

-  There is no specific therapy for the renal disease or neurologic deficits.

-  Renal treatment may include alkali therapy, phosphate replacement, and vitamin D support.

-  Cataract removal is generally required.

-  Genetic counselling.

Death occur during childhood.

- Bartter syndrome.

 Bartter syndrome

The pathogenesis:

Failure of chloride reabsorption in the thick ascending limb of the loop of Henlé,thus resembling the pharmacological effect of furosemide (frusemide)

Bartter syndrome has been associated with 5 distinct genetic defects in loop of Henle transporters:

CCD, cortisol collecting duct; DCT, descending convoluted tubule; PGE2, prostaglandin E2; TAL, thick ascending loop of Henle.

- Wolf-Hirschhorn Syndrome.

Wolf-Hirschhorn Syndrome

*Pathophysiology:-
results from deletion of the distal short arm of chromosome no 4 (1).

* Clinically, the minimal diagnostic criteria for Wolf-Hirschhorn syndrome (ie, ‘‘core’’ phenotype) consists of typical facial appearance , mental retardation, growth delay, hypotonia and seizures (or EEG anomalies)(2).

* Different categories of the Wolf-Hirschhorn syndrome phenotype are defined according to the extent of the chromosome.4 deletion(2):-

• 1st category :- caused by small deletion that is usually associated with a mild phenotype, lacking major malformations. This category is likely under-diagnosed.
• 2nd category :- caused by large deletions that cause the widely recognizable Wolf-Hirschhorn syndrome phenotype.
• 3rd category :- caused by very large deletions that cause a severe phenotype that can hardly be defined as typical Wolf-Hirschhorn syndrome.

- Down Syndrome.

Down Syndrome.

-History:-
English physician John Down first characterized Down  syndrome as a distinct form of mental disability in 1862 due to  his perception that children with Down syndrome shared physical  facial similarities (epicanthal folds) with those of Mongolian race.

-Incidence:-

• In general population 1:660.
• It is the most common Autosomal abnormalities.
• It has equal sex distribution.

-Causes (cytogenic types):-

1-Complete Trisomy 21 (non disjunction):-

• Incidence:- 95%.
• Due to non-disjunction of chromosome 21 during meiotic division (  (i.e failure of a chromosome 21 pair to separate) so an ovum with 24 chromosomes when fertilized by a sperm carrying 23 chromosomes lead to formation of a fertilized ovum with 47 chromosome.
• It occur during oogenesis more than spermatgenesis.
• The risk increases with age of the pregnant mother especially  over 40years as the primary oocytes of the mother have satyed in the prophase for a long time ( 40 years or more).
• Karyotyping:- 

47,xx+21(female down).
47,xy+21(male down).
(+ means that an extra chromosome is present).

- Paediatric syndromes.

A Medical syndrome is defined as :- 
A group of symptoms and signs that collectively indicate or characterize a disease, psychological disorder, or other abnormal condition. There are a lot of medical syndromes and we try to list some of them:-

1. Down syndrome (click here).
2. Wolf-Hirschhorn Syndrome (click here).
3. Bartter syndrome (click here).
4. Liginac syndrome (click here) 
5. Lowe syndrome (click here)
6. Alport syndrome (click here)