Incontinentia pigmenti

Incontinentia pigmenti
Classification and external resources
Specialty	medical genetics
ICD-10	Q82.3
ICD-9-CM	757.33
OMIM	308300
DiseasesDB	29600
MedlinePlus	001583
eMedicine	article/1114205 article/1176285
MeSH	D007184
GeneReviews	Incontinentia pigmenti
Orphanet	464

Incontinentia pigmenti (IP, also known as "Bloch–Siemens syndrome,"^[1] "Bloch–Sulzberger disease,"^[2] "Bloch–Sulzberger syndrome"^[1] "melanoblastosis cutis," and "nevus pigmentosus systematicus") is a genetic disorder that affects the skin, hair, teeth, nails, and central nervous system. It is named due to its microscopic appearance.

Presentation

Incontinentia pigmenti forming along Blaschko's lines in a 3-year-old girl.

The skin lesions evolve through characteristic stages:

blistering (from birth to about four months of age),
a wart-like rash (for several months),
swirling macular hyperpigmentation (from about six months of age into adulthood), followed by
linear hypopigmentation.

Alopecia, hypodontia, abnormal tooth shape, and dystrophic nails are observed. Some patients have retinal vascular abnormalities predisposing to retinal detachment in early childhood. Cognitive delays/mental retardation are occasionally seen.

Discolored skin is caused by excessive deposits of melanin (normal skin pigment). Most newborns with IP will develop discolored skin within the first two weeks. The pigmentation involves the trunk and extremities, is slate-grey, blue or brown, and is distributed in irregular marbled or wavy lines. The discoloration sometimes fades with age.

Neurological problems can include: cerebral atrophy, the formation of small cavities in the central white matter of the brain, and the loss of neurons in the cerebellar cortex. About 20% of children with IP will have slow motor development, muscle weakness in one or both sides of the body, mental retardation, and seizures. They are also likely to have visual problems, which can include: crossed eyes, cataracts, and severe visual loss. Dental problems are common, and include missing or peg-shaped teeth - patients with IP often keep milk teeth into adult life.

Breast anomalies can occur in 1% of patients; anomalies can include hypoplasia and supernumerary nipples.

Skeletal and structural anomalies can occur in approximately 14% of patients, including:

Somatic asymmetry,
Hemivertebrae,
Scoliosis,
Spina bifida,
Syndactyly,
Acheiria (congenital absence of the hands - note: other limbs may be affected),
Ear anomalies,
Extra ribs,
Skull deformities,
Primary pulmonary hypertension,
Cardiopulmonary failure

Genetics

IP is inherited in an X-linked dominant manner.^[3]^[4] IP is lethal in most, but not all, males. A female with IP may have inherited the IKBKG mutation from either parent or have a new gene mutation. Parents may either be clinically affected or have germline mosaicism. Affected women have a 50% risk of transmitting the mutant IKBKG allele at conception; however, most affected male conceptuses miscarry. Thus, the expected ratio for liveborn children is 33% unaffected females, 33% affected females, and 33% unaffected males. Genetic counseling, prenatal testing, and preimplantation genetic diagnosis is available.

In females, the cells expressing the mutated IKBKG gene due to lyonization selectively die around the time of birth so the X-inactivation is extremely skewed.^[5]

IP is caused by mutations in a gene called NEMO (NF-κB essential modulator).

Diagnosis

The diagnosis of IP is established by clinical findings and occasionally by corroborative skin biopsy. Molecular genetic testing of the NEMO IKBKG gene (chromosomal locus Xq28) reveals disease-causing mutations in about 80% of probands. Such testing is available clinically.

In addition, females with IP have skewed X-chromosome inactivation; testing for this can be used to support the diagnosis.

Many people in the past were misdiagnosed with a second type of IP, formerly known as IP1. This has now been given its own name - 'Hypomelanosis of Ito' (incontinentia pigmenti achromians). This has a slightly different presentation: swirls or streaks of hypopigmentation and depigmentation. It is not inherited and does not involve skin stages 1 or 2. Some 33–50% of patients have multisystem involvement — eye, skeletal, and neurological abnormalities. Its chromosomal locus is at Xp11, rather than Xq28.

History

This disorder was first reported by Bruno Bloch, a German dermatologist in 1926 and Marion Sulzberger, an American dermatologist in 1928.^[6]^[7]^[8]

References

1 2 Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. ISBN 1-4160-2999-0.
↑ M. B. Sulzberger (1927). Über eine bisher nicht beschriebene kongenitale Pigmentanomalie (incontinentia pigmenti).. Berlin: Archiv für Dermatologie und Syphilis. p. 154.
↑ Pettigrew R, Kuo HC, Scriven P, et al. (December 2000). "A pregnancy following PGD for X-linked dominant [correction of X-linked autosomal dominant] incontinentia pigmenti (Bloch-Sulzberger syndrome): case report". Hum. Reprod. 15 (12): 2650–2. doi:10.1093/humrep/15.12.2650. PMID 11098039.
↑ "Incontinentia pigmenti. DermNet NZ".
↑ Smahi A, Courtois G, Vabres P, et al. (2000). "Genomic rearrangement in NEMO impairs NF-kappaB activation and is a cause of incontinentia pigmenti. The International Incontinentia Pigmenti (IP) Consortium". Nature. 405 (6785): 466–72. doi:10.1038/35013114. PMID 10839543.
↑ Bloch-Sulzberger pigment dermatosis (Bruno Bloch) at Who Named It?
↑ Bloch, B. (1926). "Eigentümliche, bisher nicht beschriebene Pigmentaffektion (incontinentia pigmenti)". Schweizerische medizinische Wochenschrift. Basel. 56: 404–5.
↑ Sulzberger, M.B. (1927). "Über eine bisher nicht beschriebene kongenitale Pigmentanomalie (incontinentia pigmenti)". Archiv für Dermatologie und Syphilis. Berlin. 154: 19–32. doi:10.1007/bf01828398.

External links

Congenital malformations and deformations of integument / skin disease (Q80–Q82, 757.0–757.3)

Genodermatosis

Congenital ichthyosis/
erythrokeratodermia

AD	Ichthyosis vulgaris

AR	Congenital ichthyosiform erythroderma: Epidermolytic hyperkeratosis Lamellar ichthyosis Harlequin type ichthyosis Netherton syndrome Zunich–Kaye syndrome Sjögren–Larsson syndrome

XR	X-linked ichthyosis

Ungrouped	Ichthyosis bullosa of Siemens Ichthyosis follicularis Ichthyosis prematurity syndrome Ichthyosis–sclerosing cholangitis syndrome Nonbullous congenital ichthyosiform erythroderma Ichthyosis linearis circumflexa Ichthyosis hystrix

EB
and related

EBS
- EBS-K
- EBS-WC
- EBS-DM
- EBS-OG
- EBS-MD
- EBS-MP

DEB
- DDEB
- RDEB

Ectodermal dysplasia

Elastic/Connective

Hyperkeratosis/
keratinopathy

PPK	diffuse: Diffuse epidermolytic palmoplantar keratoderma Diffuse nonepidermolytic palmoplantar keratoderma Palmoplantar keratoderma of Sybert Mal de Meleda syndromic connexin Bart–Pumphrey syndrome Clouston's hidrotic ectodermal dysplasia Vohwinkel syndrome Corneodermatoosseous syndrome plakoglobin Naxos syndrome Scleroatrophic syndrome of Huriez Olmsted syndrome Cathepsin C Papillon–Lefèvre syndrome Haim–Munk syndrome Camisa disease focal: Focal palmoplantar keratoderma with oral mucosal hyperkeratosis Focal palmoplantar and gingival keratosis Howel–Evans syndrome Pachyonychia congenita Pachyonychia congenita type I Pachyonychia congenita type II Striate palmoplantar keratoderma Tyrosinemia type II punctate: Acrokeratoelastoidosis of Costa Focal acral hyperkeratosis Keratosis punctata palmaris et plantaris Keratosis punctata of the palmar creases Schöpf–Schulz–Passarge syndrome Porokeratosis plantaris discreta Spiny keratoderma ungrouped: Palmoplantar keratoderma and spastic paraplegia desmoplakin Carvajal syndrome connexin Erythrokeratodermia variabilis HID/KID

Other	Meleda disease Keratosis pilaris ATP2A2 Darier's disease Dyskeratosis congenita Lelis syndrome Dyskeratosis congenita Keratolytic winter erythema Keratosis follicularis spinulosa decalvans Keratosis linearis with ichthyosis congenital and sclerosing keratoderma syndrome Keratosis pilaris atrophicans faciei Keratosis pilaris

Other

see also Template:Congenital malformations and deformations of skin appendages, Template:Phakomatoses, Template:Pigmentation disorders, Template:DNA replication and repair-deficiency disorder

Developmental
anomalies

Midline	Dermoid cyst Encephalocele Nasal glioma PHACE association Sinus pericranii

Nevus	Capillary hemangioma Port-wine stain Nevus flammeus nuchae

Other/ungrouped	Aplasia cutis congenita Amniotic band syndrome Branchial cyst Cavernous venous malformation Accessory nail of the fifth toe Bronchogenic cyst Congenital cartilaginous rest of the neck Congenital hypertrophy of the lateral fold of the hallux Congenital lip pit Congenital malformations of the dermatoglyphs Congenital preauricular fistula Congenital smooth muscle hamartoma Cystic lymphatic malformation Median raphe cyst Melanotic neuroectodermal tumor of infancy Mongolian spot Nasolacrimal duct cyst Omphalomesenteric duct cyst Poland anomaly Rapidly involuting congenital hemangioma Rosenthal–Kloepfer syndrome Skin dimple Superficial lymphatic malformation Thyroglossal duct cyst Verrucous vascular malformation Birthmark

Phakomatosis (Q85, 759.5–759.6)

Angiomatosis	Sturge–Weber syndrome Von Hippel–Lindau disease

Hamartoma	Tuberous sclerosis Hypothalamic hamartoma (Pallister–Hall syndrome) Multiple hamartoma syndrome Proteus syndrome Cowden syndrome Bannayan–Riley–Ruvalcaba syndrome Lhermitte–Duclos disease

Neurofibromatosis	Type I Type II

Other	Abdallat–Davis–Farrage syndrome Ataxia telangiectasia Incontinentia pigmenti Peutz–Jeghers syndrome

Sex linkage: X-linked disorders

X-linked recessive

Immune	Chronic granulomatous disease (CYBB) Wiskott–Aldrich syndrome X-linked severe combined immunodeficiency X-linked agammaglobulinemia Hyper-IgM syndrome type 1 IPEX X-linked lymphoproliferative disease Properdin deficiency

Hematologic	Haemophilia A Haemophilia B X-linked sideroblastic anemia

Endocrine	Androgen insensitivity syndrome/Spinal and bulbar muscular atrophy KAL1 Kallmann syndrome X-linked adrenal hypoplasia congenita

Metabolic	Amino acid: Ornithine transcarbamylase deficiency Oculocerebrorenal syndrome Dyslipidemia: Adrenoleukodystrophy Carbohydrate metabolism: Glucose-6-phosphate dehydrogenase deficiency Pyruvate dehydrogenase deficiency Danon disease/glycogen storage disease Type IIb Lipid storage disorder: Fabry's disease Mucopolysaccharidosis: Hunter syndrome Purine-pyrimidine metabolism: Lesch–Nyhan syndrome Mineral: Menkes disease/Occipital horn syndrome

Nervous system	X-linked mental retardation: Coffin–Lowry syndrome MASA syndrome Alpha-thalassemia mental retardation syndrome Siderius X-linked mental retardation syndrome Eye disorders: Color blindness (red and green, but not blue) Ocular albinism (1) Norrie disease Choroideremia Other: Charcot–Marie–Tooth disease (CMTX2-3) Pelizaeus–Merzbacher disease SMAX2

Skin and related tissue	Dyskeratosis congenita Hypohidrotic ectodermal dysplasia (EDA) X-linked ichthyosis X-linked endothelial corneal dystrophy

Neuromuscular	Becker's muscular dystrophy/Duchenne Centronuclear myopathy (MTM1) Conradi–Hünermann syndrome Emery–Dreifuss muscular dystrophy 1

Urologic	Alport syndrome Dent's disease X-linked nephrogenic diabetes insipidus

Bone/tooth	AMELX Amelogenesis imperfecta

No primary system	Barth syndrome McLeod syndrome Smith–Fineman–Myers syndrome Simpson–Golabi–Behmel syndrome Mohr–Tranebjærg syndrome Nasodigitoacoustic syndrome

X-linked dominant

X-linked hypophosphatemia Focal dermal hypoplasia Fragile X syndrome Aicardi syndrome Incontinentia pigmenti Rett syndrome CHILD syndrome Lujan–Fryns syndrome Orofaciodigital syndrome 1 Craniofrontonasal dysplasia

Deficiencies of intracellular signaling peptides and proteins

GTP-binding protein regulators

GTPase-activating protein	Neurofibromatosis type I Watson syndrome Tuberous sclerosis

Guanine nucleotide exchange factor	Marinesco–Sjögren syndrome Aarskog–Scott syndrome Juvenile primary lateral sclerosis X-Linked mental retardation 1

G protein

Heterotrimeic	cAMP/GNAS1: Pseudopseudohypoparathyroidism Progressive osseous heteroplasia Pseudohypoparathyroidism Albright's hereditary osteodystrophy McCune–Albright syndrome CGL 2

Monomeric	RAS: HRAS Costello syndrome KRAS Noonan syndrome 3 KRAS Cardiofaciocutaneous syndrome RAB: RAB7 Charcot–Marie–Tooth disease RAB23 Carpenter syndrome RAB27 Griscelli syndrome type 2 RHO: RAC2 Neutrophil immunodeficiency syndrome ARF: SAR1B Chylomicron retention disease ARL13B Joubert syndrome 8 ARL6 Bardet–Biedl syndrome 3

MAP kinase

Cardiofaciocutaneous syndrome

Other kinase/phosphatase

Tyrosine kinase	BTK X-linked agammaglobulinemia ZAP70 ZAP70 deficiency

Serine/threonine kinase	RPS6KA3 Coffin-Lowry syndrome CHEK2 Li-Fraumeni syndrome 2 IKBKG Incontinentia pigmenti STK11 Peutz–Jeghers syndrome DMPK Myotonic dystrophy 1 ATR Seckel syndrome 1 GRK1 Oguchi disease 2 WNK4/WNK1 Pseudohypoaldosteronism 2

Tyrosine phosphatase	PTEN Bannayan–Riley–Ruvalcaba syndrome Lhermitte–Duclos disease Cowden syndrome Proteus-like syndrome MTM1 X-linked myotubular myopathy PTPN11 Noonan syndrome 1 LEOPARD syndrome Metachondromatosis

Signal transducing adaptor proteins

Other

NF2
- Neurofibromatosis type II
NOTCH3
- CADASIL
PRKAR1A
- Carney complex
PRKAG2
- Wolff–Parkinson–White syndrome
PRKCSH
- PRKCSH Polycystic liver disease
XIAP
- XIAP2

See also intracellular signaling peptides and proteins

Pigmentation disorders/Dyschromia (L80–L81, 709.0)

Hypo-/
leucism

Loss of
melanocytes

Vitiligo	Quadrichrome vitiligo Vitiligo ponctué

Syndromic	Alezzandrini syndrome Vogt–Koyanagi–Harada syndrome

Melanocyte development	Piebaldism Waardenburg syndrome Tietz syndrome

Loss of melanin/
amelanism

Albinism	Oculocutaneous albinism Ocular albinism

Melanosome transfer	Hermansky–Pudlak syndrome Chédiak–Higashi syndrome Griscelli syndrome Elejalde syndrome Griscelli syndrome type 2 Griscelli syndrome type 3

Other	Cross syndrome ABCD syndrome Albinism–deafness syndrome Idiopathic guttate hypomelanosis Phylloid hypomelanosis Progressive macular hypomelanosis

Leukoderma w/o
hypomelanosis

Ungrouped

Hyper-

Melanin/
Melanosis/
Melanism

Reticulated	Dermatopathia pigmentosa reticularis Pigmentatio reticularis faciei et colli Reticulate acropigmentation of Kitamura Reticular pigmented anomaly of the flexures Naegeli–Franceschetti–Jadassohn syndrome Dyskeratosis congenita X-linked reticulate pigmentary disorder Galli–Galli disease Revesz syndrome

Diffuse/ circumscribed	Lentigo/Lentiginosis: Lentigo simplex Liver spot Centrofacial lentiginosis Generalized lentiginosis Inherited patterned lentiginosis in black persons Ink spot lentigo Lentigo maligna Mucosal lentigines Partial unilateral lentiginosis PUVA lentigines Melasma Erythema dyschromicum perstans Lichen planus pigmentosus Café au lait spot Poikiloderma (Poikiloderma of Civatte Poikiloderma vasculare atrophicans) Riehl melanosis

Linear	Incontinentia pigmenti Scratch dermatitis Shiitake mushroom dermatitis

Other/ ungrouped	Acanthosis nigricans Freckle Familial progressive hyperpigmentation Pallister–Killian syndrome Periorbital hyperpigmentation Photoleukomelanodermatitis of Kobori Postinflammatory hyperpigmentation Transient neonatal pustular melanosis

Other
pigments

Iron	Hemochromatosis Iron metallic discoloration Pigmented purpuric dermatosis Schamberg disease Majocchi's disease Gougerot–Blum syndrome Doucas and Kapetanakis pigmented purpura/Eczematid-like purpura of Doucas and Kapetanakis Lichen aureus Angioma serpiginosum Hemosiderin hyperpigmentation

Other metals	Argyria Chrysiasis Arsenic poisoning Lead poisoning Titanium metallic discoloration

Other	Carotenosis Tattoo Tar melanosis

Dyschromia