Distichiasis may be congenital or acquired. Although metaplasia of the meibomian glands due to a long-standing cicatrizing eyelid and ocular surface disease is probably responsible for acquired distichiasis,³ it is the congenital variety that deserves special mention. The congenital variety, which is termed lymphedema-distichiasis (LD) syndrome, is a dominantly inherited disorder with high penetrance and variable expressivity, but it may also occur de novo, with an estimated rate of new-onset mutations of around 30%.⁴ LD syndrome typically presents with distichiasis at birth and lymphedema at puberty,⁵,⁶ and males suffer the greater brunt of this disease.⁶ Embryologically, the meibomian gland analgen, which are a derivative of the surface ectoderm, appear around week 11. It is important to understand that early during embryonic life, the meibomian gland analgen are fundamentally similar to the eyelash analgen, albeit developing in a much slower fashion.⁷ This embryologic mimicry is the reason why the meibomian glands are sometimes referred to as a “hair follicle without a hair shaft.”⁸ According to Samuel Whitnall, the occurrence of congenital distichiasis should not be surprising because the meibomian glands represent a primitive vestigial remnant of a secondary row of eyelashes that have disappeared in humans during evolution.⁹ Congenital distichiasis, therefore, is probably an atavistic phenomenon that develops when the primary epithelial germ cells in the meibomian gland analgen develop into a complete pilosebaceous unit instead of a specialized tarsal gland.¹⁰,¹¹,¹²

In 1999, the gene for LD syndrome was identified as the FOXC2 gene and mapped to chromosome 16q24.¹³ Several mutations have been reported in the FOXC2 gene, a forkhead transcription factor gene, formerly known as the mesenchyme forkhead 1 (MFH1) gene, which as of the time of this writing is the only gene decisively linked to LD syndrome.¹⁴,¹⁵ Recent evidence from animal knockout mutation models suggests that FOXC2 is normally expressed in the endothelial and smooth muscle cells of developing venous and lymphatic vessels, particularly the valvular leaflets, which control vascular outflow.¹⁶,¹⁷,¹⁸,¹⁹ It is also expressed in neural crest-derived mesenchymal cells, and is necessary for normal meibomian gland development through mechanisms that are not yet entirely clear.²⁰,²¹ It should be noted that abnormalities in the FOXC2 gene not only affect the meibomian glands but may also result in abnormal thickening of the corneal stroma, corneal neovascularization, as well as corneal conjunctivalization.²⁰ Therefore, some of the symptoms encountered in patients with congenital distichiasis, such as photophobia, may be due to corneal abnormalities and may not be entirely attributable to rubbing lashes.

Although patients with LD syndrome are born with distichiatic lashes, they typically present around the age of 4 or 5 years and not at birth. This is because these lashes are initially lanugo-like, finer, thinner, well-tolerated and may
not cause ocular irritation at the outset.¹,⁶,¹¹ Occasionally, distichiasis could be accidently discovered earlier by the ophthalmologist or even by an observant parent who occasionally may present with the child commenting on the presence of a double row of lashes parallel to each other. As the child grows, the patient may experience significant photophobia and ocular irritation symptoms. The aberrant eyelashes may be represented by a few cilia forming a discontinuous row or as a regular well-formed row parallel to the normal eyelashes (Figure 30.1A).⁶ Lashes can be observed growing out of the meibomian gland orifices near the posterior lid margin. These lashes are straight, pigmented, and rub against the cornea. The aberrant eyelashes are more commonly observed emerging from all four eyelids,²² but occasionally they may be seen emerging exclusively from the lower or upper eyelids.¹,²² Distichiatic lashes in patients with LD syndrome are more common in the central and lateral parts of the eyelid than in the medial part.⁶ Other ocular associations include blepharophimosis syndrome, blepharoptosis, strabismus, and rarely keratoconus.⁶,²²

Primary lymphedema, which is the second cardinal symptom of LD syndrome, is also highly penetrant but usually develops around the age of 10 years in males and even later in females.⁶ This is the reason why distichiasis may present in clinical practice without lymphedema and may have led some authors to contemplate the occurrence of distichiasis in isolation without lymphedema, a scenario that is rejected by geneticists.⁶,¹⁰,²³

Because FOXC2 mutations affect both lymphatic and venous morphogenesis, patients with LD syndrome suffer not only from lymphedema but from varicose veins as well. This affects up to 50% of individuals with LD syndrome,⁶ and even if not clinically evident, a recent color Duplex ultrasound study has shown that every single participant with a mutation in FOXC2 showed reflux in the great saphenous vein.¹⁷ Other systemic associations include congenital heart disease (ventricular septal defect, tetralogy of Fallot, or patent ductus arteriosus, 6.8%), cleft lip and/or palate (4%), and less commonly scoliosis, renal abnormalities, spinal epidural cysts, learning difficulties, and autism.⁶,¹⁴,²⁴

Acquired distichiasis (Figure 30.1B and C) may be observed as an intermediate or long-term sequela of chronic inflammatory conditions in the eyelids, like ocular cicatricial pemphigoid, Stevens-Johnson syndrome, trachoma, or following chemical injuries, but they rarely if ever form a regular row of lashes, and contrary to congenital distichiasis, these lashes tend to be shorter, finer, nonpigmented, or faintly pigmented.¹¹,²⁵ Recently PTD combination chemotherapy (pertuzumab + trastuzumab + docetaxel) in a patient with HER2-positive metastatic breast cancer resulted in bilateral lower eyelid distichiasis and mild cicatricial lower eyelid entropion as an ocular side effect.²⁶ The specific chemotherapeutic agent responsible for the eyelid changes is unknown but docetaxel is the likely culprit.²⁷