Naegeli-Franceschetti-Jadassohn Syndrome Clinical Presentation
- Author: Rebekah H Clifford, MD; Chief Editor: Dirk M Elston, MD more...
Compared with reticulate hyperpigmentation, which fades, hypohidrosis and palmoplantar keratoderma usually persist in Naegeli-Franceschetti-Jadassohn (NFJ) syndrome. In a reexamination of the original family, the natural history of the syndrome was described. The pedigree now documents findings in 6 generations including 62 members with 14 persons affected by NFJ syndrome.
Further data have been accumulated from the original family with NFJ syndrome. Mevorah et al examined 2 patients and documented a mild reduction in the number of functional sweat glands when they were exposed to moderate heat stress. However, the patients remained comfortable and had normal thermal regulation. In addition, Frenk et al performed an electron microscopic study of skin samples from 2 members in the original family. Pigment incontinence was accompanied by varying amounts of colloid-amyloid bodies in the papillar dermis and occasionally around sweat glands in the reticular dermis. This finding is also described in incontinentia pigmenti.
The main syndrome of Naegeli-Franceschetti-Jadassohn (NFJ) syndrome, an ectodermal dysplasia, is heat intolerance worsened by reduced sweating, with a potential to cause collapse, flushing, and dizziness after even mild exercise. Clinically, patients lack dermatoglyphics, or fingerprint lines, as shown below.
Patients also have a characteristic reticular pigmentation, without a preceding inflammatory stage, on their neck, chest, and abdomen, that begins when they are aged 1-5 years and improves after puberty. In many cases, the pigmentation completely resolves at adolescence. In addition, increased spotlike pigmentation may be present around the mouth and eyes. Note the images below.
Affected individuals have mild palmoplantar keratosis, depicted below, brittle fingernails, and defective tooth enamel with a rough surface and yellow spots (shown below). Many patients may develop complete loss of adult teeth.[6, 7, 8]
To date, all patients reported had normal intelligence and were usually in good health. Malalignment of the great toenails, bullae, and periungual and mucosal pigmentation are only rarely observed.[8, 9]
Several slightly different clinical phenotypes and intrafamilial variability are also reported.[8, 10, 11, 12, 9, 13, 14] An additional patient with greater variation from the phenotype was identified in Greece. In this patient's family, the reticular hyperpigmentation was accentuated on the flexural areas of the arms and legs; neck; axillae; and cruroinguinal, antecubital, and popliteal regions, where extensive milia formation was observed. The formation of milia had not been reported in the other patients. In the father and grandfather of this patient, the generalized reticular hyperpigmentation was reported to have faded in adulthood. The hyperpigmented macules varied in color (brown to black), pattern, and distribution. Some of the macules were frecklelike or angulated, and they tended to form a reticulate pattern. Others had a mottled pattern or formed streaks and whorls.
Wittock et al studied a single family of British origin, identifying 25 members that are affected by Naegeli-Franceschetti-Jadassohn (NFJ) syndrome and 37 that are unaffected. Markers located on arms 1q, 12q, and 18q were excluded for links to the disease; this finding indicates that the gene for NFJ syndrome is not located in the epidermal differentiation complex, the type II keratin cluster, or the desmosomal cadherin cluster, respectively.
In contrast, a highly significant linkage was detected with a number of markers located in the vicinity of the type I keratin gene cluster on band 17q21, with maximum 2-lod scores of 4.16 and 3.717 for the markers D17S1787 and D17S1886, respectively. The genetic defect appears to be a region of the gene encoding the KRT14 nonhelical head (E1/V1) domain located between the microsatellite markers D17S798 and D17S957, which are separated by approximately 26.97 cM. A nonsense mutation in a corresponding region of KRT5 has been found in Dowling-Degos disease and a missense mutation in the V1 domain of KRT5 has been described in patients with epidermolysis bullosa with mottled pigmentation. These observations support a mutation in a basal keratin gene as causing both blistering and pigmentary disorders.[1, 16]
While abnormal keratin filament structure and function can explain hypohidrosis and epithelial differentiation abnormalities, the absence of dermatoglyphics is not well understood. Proliferation of KRT14 -expressing basal cells leads to development of dermatoglyphics during the first trimester of gestation. KRT14 is therefore considered a candidate gene. Other candidate genes have been mapped to the region critical to NFJ syndrome; these include the granulin gene that encodes a protein involved in epithelium growth and differentiation ; frizzled homolog 2, a molecule involved in epithelial cell-signaling pathways ; ADAM-11, a protein implicated in cell-to-cell and cell-to-matrix interactions ; GRB-7, a membrane-bound growth factor receptor of uncertain function ; and the MEOX1 gene.
Studies suggest that NFJ syndrome is caused by frameshift or nonsense mutations in KRT14, leading to early termination of translation- or nonsense-mediated degradation of mRNA (50% or less), with resulting haploinsufficiency. Type I keratins have been shown to protect keratinocytes by blocking tumor necrosis factor-alpha (TNF-alpha) proapoptotic signals, likely through interaction with TNF receptor type 1 (TNFR1)–associated death domain protein (TRADD). Specifically, decreased KRT14 has been shown to lead to increased TNF-alpha–induced apoptosis of keratinocytes.[22, 23, 24, 1]
Letters by Titeux et al and Van Steensel et al call into question the hypothesis of haploinsufficiency causing the dominant effect seen in NFJ syndrome. The authors of Titeux et al studied a patient with a null mutation of KRT14 with clinical manifestations of epidermolysis bullosa simplex but with absent dermatoglyphs. The authors stipulate that the patient’s offspring are heterozygous carriers of the KRT14 null mutation and would therefore have some manifestations of NFJ syndrome, according to the haploinsufficiency hypothesis. However, the 2 healthy children displayed no pigmentation abnormalities, had normal dermatoglyphs, and had no other cutaneous findings of NFJ syndrome. The authors offer the following alternative explanations to haploinsufficiency:
The synthesis of short serine-rich peptides arising from the K14 head domain could impair its assembly.
There may be alteration of a putative noncoding RNA (ncRNA) arising from the 5′ terminus of KRT14.
Van Steensel et al describe a 41-year-old woman of Dutch descent with flexural hyperpigmentation, nail dystrophy, and reduced dermatoglyphics, but with normal sweating. She was found to have a heterozygous missense mutation in KRT14. The authors believe this case casts doubt on haploinsufficiency causing NFJ syndrome because missense mutations in keratins are considered to have a dominant negative effect, which was not observed in this case.
Lugassy J, Itin P, Ishida-Yamamoto A, et al. Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis: two allelic ectodermal dysplasias caused by dominant mutations in KRT14. Am J Hum Genet. 2006 Oct. 79(4):724-30. [Medline].
Larrègue M, Prigent F, Lorette G, Canuel C, Ramdenee P. [Bullous and hereditary Weary-Kindler's acrokeratotic poikiloderma (author's transl)]. Ann Dermatol Venereol. 1981. 108(1):69-76. [Medline].
Mevorah B, Frascarolo P, Gianadda E, Donatsch J. Sweat studies under conditions of moderate heat stress in two patients with the Nägeli-Franceschetti-Jadassohn syndrome. Dermatology. 1993. 187(3):174-7. [Medline].
Frenk E, Mevorah B, Hohl D. The Nageli-Franceschetti-Jadassohn syndrome: A hereditary ectodermal defect leading to colloid-amyloid formation in the dermis. Dermatology. 1993. 187(3):169-73. [Medline].
Zillikens D, Mehringer A, Lechner W, Burg G. Hypo- and hyperpigmented areas in incontinentia pigmenti. Light and electron microscopic studies. Am J Dermatopathol. 1991 Feb. 13(1):57-62. [Medline].
Naegeli O. Familiarer Chromnatophotennes. Schweiz Med Wochenschr. 1927. 8:48.
Franceschetti A, Jadassohn W. [On incontinentia pigmenti and differentiation of two syndromes appearing under the same name.]. Dermatologica. 1954 Jan. 108(1):1-28. [Medline].
Sparrow GP, Samman PD, Wells RS. Hyperpigmentation and hypohidrosis. (The Naegeli-Franceschetti-Jadassohn syndrome): report of a family and review of the literature. Clin Exp Dermatol. 1976 Jun. 1(2):127-40. [Medline].
Itin PH, Lautenschlager S, Meyer R, Mevorah B, Rufli T. Natural history of the Naegeli-Franceschetti-Jadassohn syndrome and further delineation of its clinical manifestations. J Am Acad Dermatol. 1993 Jun. 28(6):942-50. [Medline].
Kitamura K, Hirako T. [Two Japanese cases of a peculiar reticulous pigmentation.]. Dermatologica. 1955 Feb. 110(2):97-107. [Medline].
Levi L, Galbiati G, Ghislanzoni G. [Reticular pigmentary dermatitis of Franceschetti-Jadassohn syndrome. Case report]. G Ital Dermatol Minerva Dermatol. 1971 Jul. 46(7):319-22. [Medline].
Papini M. Sindrome di Naegeli-Franceschetti-Jadassohn. Ann Ital Dermatol Clin Sper. 1978. 32:281-292.
van Steensel MA, Lemmink HH. A missense mutation in KRT14 causing a dermatopathia pigmentosa reticularis/Naegeli-Franceschetti-Jadassohn phenotype. J Eur Acad Dermatol Venereol. 2010 Sep. 24(9):1116-7. [Medline].
Tubaigy SM, Hassan HM. Naegeli-Franceschetti-Jadassohn syndrome in a Saudi Arabian family. J Forensic Sci. 2014 Mar. 59(2):555-8. [Medline].
Tzermias C, Zioga A, Hatzis I. Reticular pigmented genodermatosis with milia--a special form of Naegeli-Franceschetti-Jadassohn syndrome or a new entity?. Clin Exp Dermatol. 1995 Jul. 20(4):331-5. [Medline].
Whittock NV, Coleman CM, McLean WH, et al. The gene for Naegeli-Franceschetti-Jadassohn syndrome maps to 17q21. J Invest Dermatol. 2000 Oct. 115(4):694-8. [Medline].
Bhandari V, Bateman A. Structure and chromosomal location of the human granulin gene. Biochem Biophys Res Commun. 1992 Oct 15. 188(1):57-63. [Medline].
Zhao Z, Lee CC, Baldini A, Caskey CT. A human homologue of the Drosophila polarity gene frizzled has been identified and mapped to 17q21.1. Genomics. 1995 May 20. 27(2):370-3. [Medline].
Emi M, Katagiri T, Harada Y, et al. A novel metalloprotease/disintegrin-like gene at 17q21.3 is somatically rearranged in two primary breast cancers. Nat Genet. 1993 Oct. 5(2):151-7. [Medline].
Margolis B, Silvennoinen O, Comoglio F, et al. High-efficiency expression/cloning of epidermal growth factor-receptor-binding proteins with Src homology 2 domains. Proc Natl Acad Sci U S A. 1992 Oct 1. 89(19):8894-8. [Medline]. [Full Text].
Froelich S, Houlden H, Rizzu P, et al. Construction of a detailed physical and transcript map of the FTDP-17 candidate region on chromosome 17q21. Genomics. 1999 Sep 1. 60(2):129-36. [Medline].
Whiting DA. Naegeli´s reticular pigmented dermatosis. Br J Dermatol. 1971. 85:71-73.
Lugassy J, McGrath JA, Itin P, et al. KRT14 haploinsufficiency results in increased susceptibility of keratinocytes to TNF-alpha-induced apoptosis and causes Naegeli-Franceschetti-Jadassohn syndrome. J Invest Dermatol. 2008 Jun. 128(6):1517-24. [Medline].
Dereure O. [Naegeli-Franceschetti-Jadassohn syndrome and dermatopathia pigmentosa reticularis. Two allelic ectodermal dysplasias related to mutations of dominant gene coding for keratin 14]. Ann Dermatol Venereol. 2007 Jun-Jul. 134(6-7):595. [Medline].
Titeux M, Décha A, Pironon N, et al. A new case of keratin 14 functional knockout causes severe recessive EBS and questions the haploinsufficiency model of Naegeli-Franceschetti-Jadassohn syndrome. J Invest Dermatol. 2011 Oct. 131(10):2131-3. [Medline].
Engman MF. Congenital atrophy of the skin with reticular pigmentation. JAMA. 1935. 103:1252-6.
Fulk CS. Primary disorders of hyperpigmentation. J Am Acad Dermatol. 1984 Jan. 10(1):1-16. [Medline].
Griffiths WA. Reticulate pigmentary disorders--a review. Clin Exp Dermatol. 1984 Sep. 9(5):439-50. [Medline].
Heimer WL 2nd, Brauner G, James WD. Dermatopathia pigmentosa reticularis: a report of a family demonstrating autosomal dominant inheritance. J Am Acad Dermatol. 1992 Feb. 26(2 Pt 2):298-301. [Medline].
Kudo Y, Fujiwara S, Takayasu S, Ooki H, Ogawa A. Reticulate pigmentary dermatosis associated with hypohydrosis and short stature: a variant of Naegeli-Franceschetti-Jadassohn syndrome?. Int J Dermatol. 1995 Jan. 34(1):30-1. [Medline].
Maso MJ, Schwartz RA, Lambert WC. Dermatopathia pigmentosa reticularis. Arch Dermatol. 1990 Jul. 126(7):935-9. [Medline].
Rebora A, Crovato F. The spectrum of Dowling-Degos disease. Br J Dermatol. 1984 May. 110(5):627-30. [Medline].
Schnur RE, Heymann WR. Reticulate hyperpigmentation. Semin Cutan Med Surg. 1997 Mar. 16(1):72-80. [Medline].
Tidman MJ, Wells RS, MacDonald DM. Pachyonychia congenita with cutaneous amyloidosis and hyperpigmentation--a distinct variant. J Am Acad Dermatol. 1987 May. 16(5 Pt 1):935-40. [Medline].
Zinsser F. Atrophia curis reticularis cum pigmentatione, dystrophia et leukoplakia oris. Ikonogr Dermat. 1910. 5:219-223.